Full text data of MIF
MIF
(GLIF, MMIF)
[Confidence: low (only semi-automatic identification from reviews)]
Macrophage migration inhibitory factor; MIF; 5.3.2.1 (Glycosylation-inhibiting factor; GIF; L-dopachrome isomerase; L-dopachrome tautomerase; 5.3.3.12; Phenylpyruvate tautomerase)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Macrophage migration inhibitory factor; MIF; 5.3.2.1 (Glycosylation-inhibiting factor; GIF; L-dopachrome isomerase; L-dopachrome tautomerase; 5.3.3.12; Phenylpyruvate tautomerase)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
P14174
ID MIF_HUMAN Reviewed; 115 AA.
AC P14174; A5Z1R8; B2R4S3; Q2V4Y5; Q6FHV0;
DT 01-JAN-1990, integrated into UniProtKB/Swiss-Prot.
read moreDT 23-JAN-2007, sequence version 4.
DT 22-JAN-2014, entry version 167.
DE RecName: Full=Macrophage migration inhibitory factor;
DE Short=MIF;
DE EC=5.3.2.1;
DE AltName: Full=Glycosylation-inhibiting factor;
DE Short=GIF;
DE AltName: Full=L-dopachrome isomerase;
DE AltName: Full=L-dopachrome tautomerase;
DE EC=5.3.3.12;
DE AltName: Full=Phenylpyruvate tautomerase;
GN Name=MIF; Synonyms=GLIF, MMIF;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], INDUCTION, AND SUBCELLULAR LOCATION.
RX PubMed=2552447; DOI=10.1073/pnas.86.19.7522;
RA Weiser W.Y., Temple P.A., Witek-Giannotti J.S., Remold H.G.,
RA Clark S.C., David J.R.;
RT "Molecular cloning of a cDNA encoding a human macrophage migration
RT inhibitory factor.";
RL Proc. Natl. Acad. Sci. U.S.A. 86:7522-7526(1989).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], AND SUBCELLULAR LOCATION.
RX PubMed=8234256; DOI=10.1073/pnas.90.21.10056;
RA Mikayama T., Nakano T., Gomi H., Nakagawa Y., Liu Y.C., Iwamatsu A.,
RA Weiser W.Y., Ishizaka K., Sato M., Ishii Y.;
RT "Molecular cloning and functional expression of a cDNA encoding
RT glycosylation-inhibiting factor.";
RL Proc. Natl. Acad. Sci. U.S.A. 90:10056-10060(1993).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=7947826; DOI=10.1021/bi00251a025;
RA Bernhagen J., Mitchell R.A., Calandra T., Voelter W., Cerami A.,
RA Bucala R.;
RT "Purification, bioactivity, and secondary structure analysis of mouse
RT and human macrophage migration inhibitory factor (MIF).";
RL Biochemistry 33:14144-14155(1994).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=8188240; DOI=10.1006/geno.1994.1011;
RA Paralkar V., Wistow G.J.;
RT "Cloning the human gene for macrophage migration inhibitory factor
RT (MIF).";
RL Genomics 19:48-51(1994).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA].
RA Shan Z.X., Yu X.Y., Lin S.G., Lin Q.X., Fu Y.H., Tan H.H.;
RT "The effect of macrophage migration inhibitory factor in the
RT atherogenesis process.";
RL Submitted (JAN-2002) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [MRNA].
RA Wu S.H., Xie J., Shang H.X., Li Y., Zhang Z.;
RT "Amplification and expression of macrophage migration inhibitory
RT factor (MIF) in tissue of squamous carcinoma of the cervix.";
RL Submitted (MAY-2007) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RX PubMed=15461802; DOI=10.1186/gb-2004-5-10-r84;
RA Collins J.E., Wright C.L., Edwards C.A., Davis M.P., Grinham J.A.,
RA Cole C.G., Goward M.E., Aguado B., Mallya M., Mokrab Y., Huckle E.J.,
RA Beare D.M., Dunham I.;
RT "A genome annotation-driven approach to cloning the human ORFeome.";
RL Genome Biol. 5:R84.1-R84.11(2004).
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.;
RT "Cloning of human full open reading frames in Gateway(TM) system entry
RT vector (pDONR201).";
RL Submitted (MAY-2004) to the EMBL/GenBank/DDBJ databases.
RN [10]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor
RT vector.";
RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases.
RN [11]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RG NIEHS SNPs program;
RL Submitted (NOV-2005) to the EMBL/GenBank/DDBJ databases.
RN [12]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [13]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain, Lung, Skin, and Uterus;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [14]
RP PROTEIN SEQUENCE OF 2-12.
RC TISSUE=Platelet;
RX PubMed=12665801; DOI=10.1038/nbt810;
RA Gevaert K., Goethals M., Martens L., Van Damme J., Staes A.,
RA Thomas G.R., Vandekerckhove J.;
RT "Exploring proteomes and analyzing protein processing by mass
RT spectrometric identification of sorted N-terminal peptides.";
RL Nat. Biotechnol. 21:566-569(2003).
RN [15]
RP PROTEIN SEQUENCE OF 2-11.
RC TISSUE=Liver;
RX PubMed=1286669; DOI=10.1002/elps.11501301201;
RA Hochstrasser D.F., Frutiger S., Paquet N., Bairoch A., Ravier F.,
RA Pasquali C., Sanchez J.-C., Tissot J.-D., Bjellqvist B., Vargas R.,
RA Appel R.D., Hughes G.J.;
RT "Human liver protein map: a reference database established by
RT microsequencing and gel comparison.";
RL Electrophoresis 13:992-1001(1992).
RN [16]
RP PROTEIN SEQUENCE OF 3-24.
RX PubMed=7683862; DOI=10.1006/abbi.1993.1257;
RA Zeng F.Y., Weiser W.Y., Kratzin H., Stahl B., Karas M., Gabius H.J.;
RT "The major binding protein of the interferon antagonist sarcolectin in
RT human placenta is a macrophage migration inhibitory factor.";
RL Arch. Biochem. Biophys. 303:74-80(1993).
RN [17]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 10-115.
RC TISSUE=Lens;
RX PubMed=7679497; DOI=10.1073/pnas.90.4.1272;
RA Wistow G.J., Shaughnessy M., Lee D.C., Hodin J., Zelenka P.S.;
RT "A macrophage migration inhibitory factor is expressed in the
RT differentiating cells of the eye lens.";
RL Proc. Natl. Acad. Sci. U.S.A. 90:1272-1275(1993).
RN [18]
RP INTERACTION WITH COPS5, AND SUBCELLULAR LOCATION.
RX PubMed=11089976; DOI=10.1038/35041591;
RA Kleemann R., Hausser A., Geiger G., Mischke R., Burger-Kentischer A.,
RA Flieger O., Johannes F.-J., Roger T., Calandra T., Kapurniotu A.,
RA Grell M., Finkelmeier D., Brunner H., Bernhagen J.;
RT "Intracellular action of the cytokine MIF to modulate AP-1 activity
RT and the cell cycle through Jab1.";
RL Nature 408:211-216(2000).
RN [19]
RP INVOLVEMENT IN SUSCEPTIBILITY TO SYSTEMIC JUVENILE RHEUMATOID
RP ARTHRITIS.
RX PubMed=11508429;
RX DOI=10.1002/1529-0131(200108)44:8<1782::AID-ART314>3.0.CO;2-#;
RG The British peadiatric rheumatology study group;
RA Donn R.P., Shelley E., Ollier W.E.R., Thomson W.;
RT "A novel 5'-flanking region polymorphism of macrophage migration
RT inhibitory factor is associated with systemic-onset juvenile
RT idiopathic arthritis.";
RL Arthritis Rheum. 44:1782-1785(2001).
RN [20]
RP BIOPHYSICOCHEMICAL PROPERTIES.
RX PubMed=11439086; DOI=10.1042/0264-6021:3570373;
RA Tan T.H.P., Edgerton S.A.V., Kumari R., McAlister M.S.B., Roe S.M.,
RA Nagl S., Pearl L.H., Selkirk M.E., Bianco A.E., Totty N.F.,
RA Engwerda C., Gray C.A., Meyer D.J., Rowe S.M.;
RT "Macrophage migration inhibitory factor of the parasitic nematode
RT Trichinella spiralis.";
RL Biochem. J. 357:373-383(2001).
RN [21]
RP INTERACTION WITH BNIPL.
RX PubMed=12681488; DOI=10.1016/S0014-5793(03)00229-1;
RA Shen L., Hu J., Lu H., Wu M., Qin W., Wan D., Li Y.-Y., Gu J.;
RT "The apoptosis-associated protein BNIPL interacts with two cell
RT proliferation-related proteins, MIF and GFER.";
RL FEBS Lett. 540:86-90(2003).
RN [22]
RP INTERACTION WITH CD74.
RX PubMed=12782713; DOI=10.1084/jem.20030286;
RA Leng L., Metz C.N., Fang Y., Xu J., Donnelly S., Baugh J.,
RA Delohery T., Chen Y., Mitchell R.A., Bucala R.;
RT "MIF signal transduction initiated by binding to CD74.";
RL J. Exp. Med. 197:1467-1476(2003).
RN [23]
RP FUNCTION, INDUCTION, AND SUBCELLULAR LOCATION.
RX PubMed=15908412; DOI=10.1128/IAI.73.6.3783-3786.2005;
RA Oddo M., Calandra T., Bucala R., Meylan P.R.A.;
RT "Macrophage migration inhibitory factor reduces the growth of virulent
RT Mycobacterium tuberculosis in human macrophages.";
RL Infect. Immun. 73:3783-3786(2005).
RN [24]
RP ROLE IN SEPSIS-RELATED DEATH.
RX PubMed=17443469; DOI=10.1086/514344;
RA Emonts M., Sweep F.C.G.J., Grebenchtchikov N., Geurts-Moespot A.,
RA Knaup M., Chanson A.L., Erard V., Renner P., Hermans P.W.M.,
RA Hazelzet J.A., Calandra T.;
RT "Association between high levels of blood macrophage migration
RT inhibitory factor, inappropriate adrenal response, and early death in
RT patients with severe sepsis.";
RL Clin. Infect. Dis. 44:1321-1328(2007).
RN [25]
RP SUBCELLULAR LOCATION, AND INTERACTION WITH USO1.
RX PubMed=19454686; DOI=10.4049/jimmunol.0803710;
RA Merk M., Baugh J., Zierow S., Leng L., Pal U., Lee S.J., Ebert A.D.,
RA Mizue Y., Trent J.O., Mitchell R., Nickel W., Kavathas P.B.,
RA Bernhagen J., Bucala R.;
RT "The Golgi-associated protein p115 mediates the secretion of
RT macrophage migration inhibitory factor.";
RL J. Immunol. 182:6896-6906(2009).
RN [26]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-78, AND MASS SPECTROMETRY.
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [27]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [28]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E.,
RA Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K.,
RA Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-
RT terminal acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [29]
RP X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS).
RX PubMed=8766818; DOI=10.1016/0014-5793(96)00553-4;
RA Sugimoto H., Suzuki M., Nakagawa A., Tanaka I., Nishihira J.;
RT "Crystal structure of macrophage migration inhibitory factor from
RT human lymphocyte at 2.1-A resolution.";
RL FEBS Lett. 389:145-148(1996).
RN [30]
RP X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS).
RX PubMed=8610159; DOI=10.1073/pnas.93.7.3007;
RA Kato Y., Muto T., Tomura T., Tsumura H., Watarai H., Mikayama T.,
RA Ishizaka K., Kuroki R.;
RT "The crystal structure of human glycosylation-inhibiting factor is a
RT trimeric barrel with three 6-stranded beta-sheets.";
RL Proc. Natl. Acad. Sci. U.S.A. 93:3007-3010(1996).
RN [31]
RP X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS).
RX PubMed=8643551; DOI=10.1073/pnas.93.11.5191;
RA Sun H.W., Bernhagen J., Bucala R., Lolis E.;
RT "Crystal structure at 2.6-A resolution of human macrophage migration
RT inhibitory factor.";
RL Proc. Natl. Acad. Sci. U.S.A. 93:5191-5196(1996).
RN [32]
RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS).
RX PubMed=10353846; DOI=10.1021/bi990306m;
RA Lubetsky J.B., Swope M., Dealwis C., Blake P., Lolis E.;
RT "Pro-1 of macrophage migration inhibitory factor functions as a
RT catalytic base in the phenylpyruvate tautomerase activity.";
RL Biochemistry 38:7346-7354(1999).
RN [33]
RP X-RAY CRYSTALLOGRAPHY (1.5 ANGSTROMS) IN COMPLEX WITH TAUTOMERASE
RP INHIBITOR, AND CATALYTIC ACTIVITY.
RX PubMed=11170644; DOI=10.1021/jm000386o;
RA Orita M., Yamamoto S., Katayama N., Aoki M., Takayama K., Yamagiwa Y.,
RA Seki N., Suzuki H., Kurihara H., Sakashita H., Takeuchi M., Fujita S.,
RA Yamada T., Tanaka A.;
RT "Coumarin and chromen-4-one analogues as tautomerase inhibitors of
RT macrophage migration inhibitory factor: discovery and X-ray
RT crystallography.";
RL J. Med. Chem. 44:540-547(2001).
RN [34]
RP X-RAY CRYSTALLOGRAPHY (1.75 ANGSTROMS) IN COMPLEX WITH
RP CARBONYLOXIME-BASED INHIBITORS, AND SUBUNIT.
RX PubMed=17526494; DOI=10.1074/jbc.M701825200;
RA Crichlow G.V., Cheng K.F., Dabideen D., Ochani M., Aljabari B.,
RA Pavlov V.A., Miller E.J., Lolis E., Al-Abed Y.;
RT "Alternative chemical modifications reverse the binding orientation of
RT a pharmacophore scaffold in the active site of macrophage migration
RT inhibitory factor.";
RL J. Biol. Chem. 282:23089-23095(2007).
RN [35]
RP X-RAY CRYSTALLOGRAPHY (1.55 ANGSTROMS) IN COMPLEX WITH THE INHIBITOR
RP N-ACETYL-P-BENZOQUINONE IMINE, SUBUNIT, AND CATALYTIC ACTIVITY.
RX PubMed=19090677; DOI=10.1021/bi8014423;
RA Crichlow G.V., Lubetsky J.B., Leng L., Bucala R., Lolis E.J.;
RT "Structural and kinetic analyses of macrophage migration inhibitory
RT factor active site interactions.";
RL Biochemistry 48:132-139(2009).
RN [36]
RP X-RAY CRYSTALLOGRAPHY (2.33 ANGSTROMS), FUNCTION, CATALYTIC ACTIVITY,
RP INTERACTION WITH CD74, MUTAGENESIS OF ASN-111, AND SUBUNIT.
RX PubMed=23776208; DOI=10.1073/pnas.1221817110;
RA Fan C., Rajasekaran D., Syed M.A., Leng L., Loria J.P., Bhandari V.,
RA Bucala R., Lolis E.J.;
RT "MIF intersubunit disulfide mutant antagonist supports activation of
RT CD74 by endogenous MIF trimer at physiologic concentrations.";
RL Proc. Natl. Acad. Sci. U.S.A. 110:10994-10999(2013).
CC -!- FUNCTION: Pro-inflammatory cytokine. Involved in the innate immune
CC response to bacterial pathogens. The expression of MIF at sites of
CC inflammation suggests a role as mediator in regulating the
CC function of macrophages in host defense. Counteracts the anti-
CC inflammatory activity of glucocorticoids. Has phenylpyruvate
CC tautomerase and dopachrome tautomerase activity (in vitro), but
CC the physiological substrate is not known. It is not clear whether
CC the tautomerase activity has any physiological relevance, and
CC whether it is important for cytokine activity.
CC -!- CATALYTIC ACTIVITY: Keto-phenylpyruvate = enol-phenylpyruvate.
CC -!- CATALYTIC ACTIVITY: L-dopachrome = 5,6-dihydroxyindole-2-
CC carboxylate.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=249 uM for phenylpyruvate;
CC KM=168 uM for p-hydroxyphenylpyruvate;
CC Vmax=2113 umol/min/mg enzyme toward phenylpyruvate;
CC Vmax=524 umol/min/mg enzyme toward p-hydroxyphenylpyruvate;
CC -!- SUBUNIT: Homotrimer. Interacts with CXCR2 extracellular domain (By
CC similarity). Interacts with the CD74 extracellular domain, COPS5
CC and BNIPL.
CC -!- INTERACTION:
CC O43521-2:BCL2L11; NbExp=5; IntAct=EBI-372712, EBI-526420;
CC -!- SUBCELLULAR LOCATION: Secreted. Cytoplasm. Note=Does not have a
CC cleavable signal sequence and is secreted via a specialized, non-
CC classical pathway. Secreted by macrophages upon stimulation by
CC bacterial lipopolysaccharide (LPS), or by M.tuberculosis antigens.
CC -!- INDUCTION: Up-regulated in concanavalin-A-treated lymphocytes. Up-
CC regulated in macrophages upon exposure to M.tuberculosis antigens.
CC -!- DISEASE: Rheumatoid arthritis systemic juvenile (RASJ)
CC [MIM:604302]: An inflammatory articular disorder with systemic-
CC onset beginning before the age of 16. It represents a subgroup of
CC juvenile arthritis associated with severe extraarticular features
CC and occasionally fatal complications. During active phases of the
CC disorder, patients display a typical daily spiking fever, an
CC evanescent macular rash, lymphadenopathy, hepatosplenomegaly,
CC serositis, myalgia and arthritis. Note=Disease susceptibility is
CC associated with variations affecting the gene represented in this
CC entry.
CC -!- MISCELLANEOUS: Serum levels of MIF are elevated in patients with
CC severe sepsis or septic shock. High levels of MIF are correlated
CC with low survival. Drugs that inhibit tautomerase activity protect
CC against death due to sepsis.
CC -!- SIMILARITY: Belongs to the MIF family.
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/mif/";
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/MIFID41365ch22q11.html";
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DR EMBL; M25639; AAA36315.1; -; mRNA.
DR EMBL; L10612; AAA35892.1; -; mRNA.
DR EMBL; Z23063; CAA80598.1; -; mRNA.
DR EMBL; L19686; AAA21814.1; -; Genomic_DNA.
DR EMBL; AF469046; AAL78635.1; -; mRNA.
DR EMBL; EF611126; ABQ95571.1; -; mRNA.
DR EMBL; CR456520; CAG30406.1; -; mRNA.
DR EMBL; AK311929; BAG34870.1; -; mRNA.
DR EMBL; CR407644; CAG28572.1; -; mRNA.
DR EMBL; CR541651; CAG46452.1; -; mRNA.
DR EMBL; BT007148; AAP35812.1; -; mRNA.
DR EMBL; DQ307455; ABB96245.1; -; Genomic_DNA.
DR EMBL; CH471095; EAW59620.1; -; Genomic_DNA.
DR EMBL; BC000447; AAH00447.1; -; mRNA.
DR EMBL; BC007676; AAH07676.1; -; mRNA.
DR EMBL; BC008914; AAH08914.1; -; mRNA.
DR EMBL; BC013976; AAH13976.1; -; mRNA.
DR EMBL; BC022414; AAH22414.1; -; mRNA.
DR EMBL; BC053376; AAH53376.1; -; mRNA.
DR EMBL; M95775; AAA36179.1; -; mRNA.
DR PIR; A48793; A48793.
DR RefSeq; NP_002406.1; NM_002415.1.
DR UniGene; Hs.407995; -.
DR PDB; 1CA7; X-ray; 2.50 A; A/B/C=2-115.
DR PDB; 1CGQ; X-ray; 2.00 A; A/B/C=3-115.
DR PDB; 1GCZ; X-ray; 1.90 A; A/B/C=2-115.
DR PDB; 1GD0; X-ray; 1.50 A; A/B/C=2-115.
DR PDB; 1GIF; X-ray; 1.90 A; A/B/C=1-115.
DR PDB; 1LJT; X-ray; 2.00 A; A/B/C=2-114.
DR PDB; 1MIF; X-ray; 2.60 A; A/B/C=1-115.
DR PDB; 1P1G; X-ray; 2.50 A; A/B/C=3-115.
DR PDB; 2OOH; X-ray; 1.85 A; A/B/C=2-115.
DR PDB; 2OOW; X-ray; 1.75 A; A/B/C=2-115.
DR PDB; 2OOZ; X-ray; 1.80 A; A/B/C=2-115.
DR PDB; 3B9S; X-ray; 1.80 A; A/B/C=2-115.
DR PDB; 3CE4; X-ray; 1.55 A; A/B/C=2-115.
DR PDB; 3DJH; X-ray; 1.25 A; A/B/C=2-115.
DR PDB; 3DJI; X-ray; 1.95 A; A/B/C/D/E/F=2-115.
DR PDB; 3HOF; X-ray; 1.90 A; A/B/C=1-115.
DR PDB; 3IJG; X-ray; 1.70 A; A/B/C=2-115.
DR PDB; 3IJJ; X-ray; 1.25 A; A/B/C=2-115.
DR PDB; 3JSF; X-ray; 1.93 A; A/B/C=2-115.
DR PDB; 3JSG; X-ray; 1.58 A; A/B/C=2-115.
DR PDB; 3JTU; X-ray; 1.86 A; A/B/C=2-115.
DR PDB; 3L5P; X-ray; 1.80 A; A/B/C=2-115.
DR PDB; 3L5R; X-ray; 1.94 A; A/B/C=2-115.
DR PDB; 3L5S; X-ray; 1.86 A; A/B/C=2-115.
DR PDB; 3L5T; X-ray; 1.86 A; A/B/C=2-115.
DR PDB; 3L5U; X-ray; 1.90 A; A/B/C=2-115.
DR PDB; 3L5V; X-ray; 1.70 A; A/B/C=2-115.
DR PDB; 3SMB; X-ray; 1.60 A; A/B/C=2-115.
DR PDB; 3SMC; X-ray; 1.80 A; A/B/C=2-115.
DR PDB; 3U18; X-ray; 1.90 A; A/B/C=2-115.
DR PDB; 4ETG; X-ray; 1.61 A; A/B/C=2-115.
DR PDB; 4EUI; X-ray; 1.70 A; A/B/C=2-115.
DR PDB; 4EVG; X-ray; 1.70 A; A/B/C=2-115.
DR PDB; 4F2K; X-ray; 1.53 A; A/B/C=2-115.
DR PDB; 4GRN; X-ray; 1.25 A; A/B/C=3-115.
DR PDB; 4GRO; X-ray; 2.00 A; A/B/C/D/E/F/G/H=3-115.
DR PDB; 4GRP; X-ray; 1.27 A; A/B/C=3-115.
DR PDB; 4GRQ; X-ray; 1.65 A; A/B/C=3-115.
DR PDB; 4GRR; X-ray; 1.47 A; A/B/C=3-115.
DR PDB; 4GRU; X-ray; 1.92 A; A/B/C=2-115.
DR PDB; 4GUM; X-ray; 2.33 A; A/B/C/D/E/F/G/H/I=2-115.
DR PDBsum; 1CA7; -.
DR PDBsum; 1CGQ; -.
DR PDBsum; 1GCZ; -.
DR PDBsum; 1GD0; -.
DR PDBsum; 1GIF; -.
DR PDBsum; 1LJT; -.
DR PDBsum; 1MIF; -.
DR PDBsum; 1P1G; -.
DR PDBsum; 2OOH; -.
DR PDBsum; 2OOW; -.
DR PDBsum; 2OOZ; -.
DR PDBsum; 3B9S; -.
DR PDBsum; 3CE4; -.
DR PDBsum; 3DJH; -.
DR PDBsum; 3DJI; -.
DR PDBsum; 3HOF; -.
DR PDBsum; 3IJG; -.
DR PDBsum; 3IJJ; -.
DR PDBsum; 3JSF; -.
DR PDBsum; 3JSG; -.
DR PDBsum; 3JTU; -.
DR PDBsum; 3L5P; -.
DR PDBsum; 3L5R; -.
DR PDBsum; 3L5S; -.
DR PDBsum; 3L5T; -.
DR PDBsum; 3L5U; -.
DR PDBsum; 3L5V; -.
DR PDBsum; 3SMB; -.
DR PDBsum; 3SMC; -.
DR PDBsum; 3U18; -.
DR PDBsum; 4ETG; -.
DR PDBsum; 4EUI; -.
DR PDBsum; 4EVG; -.
DR PDBsum; 4F2K; -.
DR PDBsum; 4GRN; -.
DR PDBsum; 4GRO; -.
DR PDBsum; 4GRP; -.
DR PDBsum; 4GRQ; -.
DR PDBsum; 4GRR; -.
DR PDBsum; 4GRU; -.
DR PDBsum; 4GUM; -.
DR ProteinModelPortal; P14174; -.
DR SMR; P14174; 2-115.
DR DIP; DIP-31137N; -.
DR IntAct; P14174; 17.
DR MINT; MINT-5000040; -.
DR STRING; 9606.ENSP00000215754; -.
DR BindingDB; P14174; -.
DR ChEMBL; CHEMBL2085; -.
DR PhosphoSite; P14174; -.
DR DMDM; 1170955; -.
DR SWISS-2DPAGE; P14174; -.
DR PaxDb; P14174; -.
DR PeptideAtlas; P14174; -.
DR PRIDE; P14174; -.
DR DNASU; 4282; -.
DR Ensembl; ENST00000215754; ENSP00000215754; ENSG00000240972.
DR GeneID; 4282; -.
DR KEGG; hsa:4282; -.
DR UCSC; uc002zyr.1; human.
DR CTD; 4282; -.
DR GeneCards; GC22P024236; -.
DR H-InvDB; HIX0041297; -.
DR HGNC; HGNC:7097; MIF.
DR HPA; CAB005284; -.
DR HPA; HPA003868; -.
DR MIM; 153620; gene.
DR MIM; 604302; phenotype.
DR neXtProt; NX_P14174; -.
DR Orphanet; 85414; Systemic-onset juvenile idiopathic arthritis.
DR PharmGKB; PA30819; -.
DR eggNOG; NOG08790; -.
DR HOGENOM; HOG000112325; -.
DR HOVERGEN; HBG003240; -.
DR InParanoid; P14174; -.
DR KO; K07253; -.
DR OMA; PDRIYIN; -.
DR OrthoDB; EOG7GXPDN; -.
DR PhylomeDB; P14174; -.
DR EvolutionaryTrace; P14174; -.
DR GeneWiki; Macrophage_migration_inhibitory_factor; -.
DR GenomeRNAi; 4282; -.
DR NextBio; 16845; -.
DR PRO; PR:P14174; -.
DR ArrayExpress; P14174; -.
DR Bgee; P14174; -.
DR CleanEx; HS_MIF; -.
DR Genevestigator; P14174; -.
DR GO; GO:0009986; C:cell surface; IDA:BHF-UCL.
DR GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0005576; C:extracellular region; IDA:UniProtKB.
DR GO; GO:0005615; C:extracellular space; IEA:UniProtKB-KW.
DR GO; GO:0042056; F:chemoattractant activity; IDA:BHF-UCL.
DR GO; GO:0005125; F:cytokine activity; IDA:UniProtKB.
DR GO; GO:0004167; F:dopachrome isomerase activity; IDA:UniProtKB.
DR GO; GO:0050178; F:phenylpyruvate tautomerase activity; IDA:MGI.
DR GO; GO:0007569; P:cell aging; IEA:Ensembl.
DR GO; GO:0008283; P:cell proliferation; IDA:UniProtKB.
DR GO; GO:0007166; P:cell surface receptor signaling pathway; IDA:UniProtKB.
DR GO; GO:0030330; P:DNA damage response, signal transduction by p53 class mediator; IEA:Ensembl.
DR GO; GO:0006954; P:inflammatory response; IEA:UniProtKB-KW.
DR GO; GO:0045087; P:innate immune response; IEA:UniProtKB-KW.
DR GO; GO:0043066; P:negative regulation of apoptotic process; IDA:UniProtKB.
DR GO; GO:0090344; P:negative regulation of cell aging; IDA:BHF-UCL.
DR GO; GO:0071157; P:negative regulation of cell cycle arrest; IDA:BHF-UCL.
DR GO; GO:0032269; P:negative regulation of cellular protein metabolic process; IEA:Ensembl.
DR GO; GO:0043518; P:negative regulation of DNA damage response, signal transduction by p53 class mediator; IDA:BHF-UCL.
DR GO; GO:0010629; P:negative regulation of gene expression; IDA:BHF-UCL.
DR GO; GO:1902166; P:negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator; IDA:BHF-UCL.
DR GO; GO:0002906; P:negative regulation of mature B cell apoptotic process; IEA:Ensembl.
DR GO; GO:0033033; P:negative regulation of myeloid cell apoptotic process; IEA:Ensembl.
DR GO; GO:0090238; P:positive regulation of arachidonic acid secretion; IEA:Ensembl.
DR GO; GO:0030890; P:positive regulation of B cell proliferation; IDA:BHF-UCL.
DR GO; GO:2000343; P:positive regulation of chemokine (C-X-C motif) ligand 2 production; IEA:Ensembl.
DR GO; GO:0050715; P:positive regulation of cytokine secretion; IDA:BHF-UCL.
DR GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; IDA:BHF-UCL.
DR GO; GO:0048146; P:positive regulation of fibroblast proliferation; IDA:BHF-UCL.
DR GO; GO:0031666; P:positive regulation of lipopolysaccharide-mediated signaling pathway; IEA:Ensembl.
DR GO; GO:0043406; P:positive regulation of MAP kinase activity; IEA:Ensembl.
DR GO; GO:0061081; P:positive regulation of myeloid leukocyte cytokine production involved in immune response; IEA:Ensembl.
DR GO; GO:0033138; P:positive regulation of peptidyl-serine phosphorylation; IDA:BHF-UCL.
DR GO; GO:0050731; P:positive regulation of peptidyl-tyrosine phosphorylation; IDA:BHF-UCL.
DR GO; GO:0061078; P:positive regulation of prostaglandin secretion involved in immune response; IEA:Ensembl.
DR GO; GO:0010739; P:positive regulation of protein kinase A signaling cascade; IDA:BHF-UCL.
DR GO; GO:0001516; P:prostaglandin biosynthetic process; IDA:UniProtKB.
DR GO; GO:0070207; P:protein homotrimerization; IPI:UniProtKB.
DR GO; GO:0043030; P:regulation of macrophage activation; NAS:UniProtKB.
DR InterPro; IPR001398; Macrophage_inhib_fac.
DR InterPro; IPR019829; Macrophage_inhib_fac_CS.
DR InterPro; IPR014347; Tautomerase/MIF_sf.
DR PANTHER; PTHR11954; PTHR11954; 1.
DR Pfam; PF01187; MIF; 1.
DR ProDom; PD004816; Macrophage_inhib_fac; 1.
DR SUPFAM; SSF55331; SSF55331; 1.
DR PROSITE; PS01158; MIF; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Complete proteome; Cytokine; Cytoplasm;
KW Direct protein sequencing; Immunity; Inflammatory response;
KW Innate immunity; Isomerase; Reference proteome; Secreted.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 115 Macrophage migration inhibitory factor.
FT /FTId=PRO_0000158062.
FT ACT_SITE 2 2 Proton acceptor; via imino nitrogen.
FT BINDING 33 33 Substrate.
FT BINDING 65 65 Substrate; via amide nitrogen.
FT BINDING 98 98 Substrate.
FT MOD_RES 78 78 N6-acetyllysine.
FT MUTAGEN 111 111 N->C: Causes formation of interchain
FT disulfide bonds with Cys-81 from another
FT subunit.
FT CONFLICT 57 59 CAL -> WAF (in Ref. 6; ABQ95571).
FT CONFLICT 67 67 K -> R (in Ref. 9; CAG46452).
FT CONFLICT 79 79 L -> Q (in Ref. 9; CAG46452).
FT CONFLICT 81 81 C -> F (in Ref. 6; ABQ95571).
FT CONFLICT 106 106 N -> S (in Ref. 1; AAA36315).
FT CONFLICT 113 113 T -> P (in Ref. 6; ABQ95571).
FT STRAND 3 10
FT HELIX 12 14
FT HELIX 19 31
FT HELIX 35 37
FT STRAND 39 43
FT STRAND 47 50
FT STRAND 58 66
FT HELIX 70 88
FT HELIX 92 94
FT STRAND 95 101
FT HELIX 104 106
FT STRAND 107 109
FT STRAND 112 114
SQ SEQUENCE 115 AA; 12476 MW; 56D51107C05286B2 CRC64;
MPMFIVNTNV PRASVPDGFL SELTQQLAQA TGKPPQYIAV HVVPDQLMAF GGSSEPCALC
SLHSIGKIGG AQNRSYSKLL CGLLAERLRI SPDRVYINYY DMNAANVGWN NSTFA
//
ID MIF_HUMAN Reviewed; 115 AA.
AC P14174; A5Z1R8; B2R4S3; Q2V4Y5; Q6FHV0;
DT 01-JAN-1990, integrated into UniProtKB/Swiss-Prot.
read moreDT 23-JAN-2007, sequence version 4.
DT 22-JAN-2014, entry version 167.
DE RecName: Full=Macrophage migration inhibitory factor;
DE Short=MIF;
DE EC=5.3.2.1;
DE AltName: Full=Glycosylation-inhibiting factor;
DE Short=GIF;
DE AltName: Full=L-dopachrome isomerase;
DE AltName: Full=L-dopachrome tautomerase;
DE EC=5.3.3.12;
DE AltName: Full=Phenylpyruvate tautomerase;
GN Name=MIF; Synonyms=GLIF, MMIF;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], INDUCTION, AND SUBCELLULAR LOCATION.
RX PubMed=2552447; DOI=10.1073/pnas.86.19.7522;
RA Weiser W.Y., Temple P.A., Witek-Giannotti J.S., Remold H.G.,
RA Clark S.C., David J.R.;
RT "Molecular cloning of a cDNA encoding a human macrophage migration
RT inhibitory factor.";
RL Proc. Natl. Acad. Sci. U.S.A. 86:7522-7526(1989).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], AND SUBCELLULAR LOCATION.
RX PubMed=8234256; DOI=10.1073/pnas.90.21.10056;
RA Mikayama T., Nakano T., Gomi H., Nakagawa Y., Liu Y.C., Iwamatsu A.,
RA Weiser W.Y., Ishizaka K., Sato M., Ishii Y.;
RT "Molecular cloning and functional expression of a cDNA encoding
RT glycosylation-inhibiting factor.";
RL Proc. Natl. Acad. Sci. U.S.A. 90:10056-10060(1993).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=7947826; DOI=10.1021/bi00251a025;
RA Bernhagen J., Mitchell R.A., Calandra T., Voelter W., Cerami A.,
RA Bucala R.;
RT "Purification, bioactivity, and secondary structure analysis of mouse
RT and human macrophage migration inhibitory factor (MIF).";
RL Biochemistry 33:14144-14155(1994).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=8188240; DOI=10.1006/geno.1994.1011;
RA Paralkar V., Wistow G.J.;
RT "Cloning the human gene for macrophage migration inhibitory factor
RT (MIF).";
RL Genomics 19:48-51(1994).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA].
RA Shan Z.X., Yu X.Y., Lin S.G., Lin Q.X., Fu Y.H., Tan H.H.;
RT "The effect of macrophage migration inhibitory factor in the
RT atherogenesis process.";
RL Submitted (JAN-2002) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [MRNA].
RA Wu S.H., Xie J., Shang H.X., Li Y., Zhang Z.;
RT "Amplification and expression of macrophage migration inhibitory
RT factor (MIF) in tissue of squamous carcinoma of the cervix.";
RL Submitted (MAY-2007) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RX PubMed=15461802; DOI=10.1186/gb-2004-5-10-r84;
RA Collins J.E., Wright C.L., Edwards C.A., Davis M.P., Grinham J.A.,
RA Cole C.G., Goward M.E., Aguado B., Mallya M., Mokrab Y., Huckle E.J.,
RA Beare D.M., Dunham I.;
RT "A genome annotation-driven approach to cloning the human ORFeome.";
RL Genome Biol. 5:R84.1-R84.11(2004).
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.;
RT "Cloning of human full open reading frames in Gateway(TM) system entry
RT vector (pDONR201).";
RL Submitted (MAY-2004) to the EMBL/GenBank/DDBJ databases.
RN [10]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor
RT vector.";
RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases.
RN [11]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RG NIEHS SNPs program;
RL Submitted (NOV-2005) to the EMBL/GenBank/DDBJ databases.
RN [12]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [13]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain, Lung, Skin, and Uterus;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [14]
RP PROTEIN SEQUENCE OF 2-12.
RC TISSUE=Platelet;
RX PubMed=12665801; DOI=10.1038/nbt810;
RA Gevaert K., Goethals M., Martens L., Van Damme J., Staes A.,
RA Thomas G.R., Vandekerckhove J.;
RT "Exploring proteomes and analyzing protein processing by mass
RT spectrometric identification of sorted N-terminal peptides.";
RL Nat. Biotechnol. 21:566-569(2003).
RN [15]
RP PROTEIN SEQUENCE OF 2-11.
RC TISSUE=Liver;
RX PubMed=1286669; DOI=10.1002/elps.11501301201;
RA Hochstrasser D.F., Frutiger S., Paquet N., Bairoch A., Ravier F.,
RA Pasquali C., Sanchez J.-C., Tissot J.-D., Bjellqvist B., Vargas R.,
RA Appel R.D., Hughes G.J.;
RT "Human liver protein map: a reference database established by
RT microsequencing and gel comparison.";
RL Electrophoresis 13:992-1001(1992).
RN [16]
RP PROTEIN SEQUENCE OF 3-24.
RX PubMed=7683862; DOI=10.1006/abbi.1993.1257;
RA Zeng F.Y., Weiser W.Y., Kratzin H., Stahl B., Karas M., Gabius H.J.;
RT "The major binding protein of the interferon antagonist sarcolectin in
RT human placenta is a macrophage migration inhibitory factor.";
RL Arch. Biochem. Biophys. 303:74-80(1993).
RN [17]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 10-115.
RC TISSUE=Lens;
RX PubMed=7679497; DOI=10.1073/pnas.90.4.1272;
RA Wistow G.J., Shaughnessy M., Lee D.C., Hodin J., Zelenka P.S.;
RT "A macrophage migration inhibitory factor is expressed in the
RT differentiating cells of the eye lens.";
RL Proc. Natl. Acad. Sci. U.S.A. 90:1272-1275(1993).
RN [18]
RP INTERACTION WITH COPS5, AND SUBCELLULAR LOCATION.
RX PubMed=11089976; DOI=10.1038/35041591;
RA Kleemann R., Hausser A., Geiger G., Mischke R., Burger-Kentischer A.,
RA Flieger O., Johannes F.-J., Roger T., Calandra T., Kapurniotu A.,
RA Grell M., Finkelmeier D., Brunner H., Bernhagen J.;
RT "Intracellular action of the cytokine MIF to modulate AP-1 activity
RT and the cell cycle through Jab1.";
RL Nature 408:211-216(2000).
RN [19]
RP INVOLVEMENT IN SUSCEPTIBILITY TO SYSTEMIC JUVENILE RHEUMATOID
RP ARTHRITIS.
RX PubMed=11508429;
RX DOI=10.1002/1529-0131(200108)44:8<1782::AID-ART314>3.0.CO;2-#;
RG The British peadiatric rheumatology study group;
RA Donn R.P., Shelley E., Ollier W.E.R., Thomson W.;
RT "A novel 5'-flanking region polymorphism of macrophage migration
RT inhibitory factor is associated with systemic-onset juvenile
RT idiopathic arthritis.";
RL Arthritis Rheum. 44:1782-1785(2001).
RN [20]
RP BIOPHYSICOCHEMICAL PROPERTIES.
RX PubMed=11439086; DOI=10.1042/0264-6021:3570373;
RA Tan T.H.P., Edgerton S.A.V., Kumari R., McAlister M.S.B., Roe S.M.,
RA Nagl S., Pearl L.H., Selkirk M.E., Bianco A.E., Totty N.F.,
RA Engwerda C., Gray C.A., Meyer D.J., Rowe S.M.;
RT "Macrophage migration inhibitory factor of the parasitic nematode
RT Trichinella spiralis.";
RL Biochem. J. 357:373-383(2001).
RN [21]
RP INTERACTION WITH BNIPL.
RX PubMed=12681488; DOI=10.1016/S0014-5793(03)00229-1;
RA Shen L., Hu J., Lu H., Wu M., Qin W., Wan D., Li Y.-Y., Gu J.;
RT "The apoptosis-associated protein BNIPL interacts with two cell
RT proliferation-related proteins, MIF and GFER.";
RL FEBS Lett. 540:86-90(2003).
RN [22]
RP INTERACTION WITH CD74.
RX PubMed=12782713; DOI=10.1084/jem.20030286;
RA Leng L., Metz C.N., Fang Y., Xu J., Donnelly S., Baugh J.,
RA Delohery T., Chen Y., Mitchell R.A., Bucala R.;
RT "MIF signal transduction initiated by binding to CD74.";
RL J. Exp. Med. 197:1467-1476(2003).
RN [23]
RP FUNCTION, INDUCTION, AND SUBCELLULAR LOCATION.
RX PubMed=15908412; DOI=10.1128/IAI.73.6.3783-3786.2005;
RA Oddo M., Calandra T., Bucala R., Meylan P.R.A.;
RT "Macrophage migration inhibitory factor reduces the growth of virulent
RT Mycobacterium tuberculosis in human macrophages.";
RL Infect. Immun. 73:3783-3786(2005).
RN [24]
RP ROLE IN SEPSIS-RELATED DEATH.
RX PubMed=17443469; DOI=10.1086/514344;
RA Emonts M., Sweep F.C.G.J., Grebenchtchikov N., Geurts-Moespot A.,
RA Knaup M., Chanson A.L., Erard V., Renner P., Hermans P.W.M.,
RA Hazelzet J.A., Calandra T.;
RT "Association between high levels of blood macrophage migration
RT inhibitory factor, inappropriate adrenal response, and early death in
RT patients with severe sepsis.";
RL Clin. Infect. Dis. 44:1321-1328(2007).
RN [25]
RP SUBCELLULAR LOCATION, AND INTERACTION WITH USO1.
RX PubMed=19454686; DOI=10.4049/jimmunol.0803710;
RA Merk M., Baugh J., Zierow S., Leng L., Pal U., Lee S.J., Ebert A.D.,
RA Mizue Y., Trent J.O., Mitchell R., Nickel W., Kavathas P.B.,
RA Bernhagen J., Bucala R.;
RT "The Golgi-associated protein p115 mediates the secretion of
RT macrophage migration inhibitory factor.";
RL J. Immunol. 182:6896-6906(2009).
RN [26]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-78, AND MASS SPECTROMETRY.
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [27]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [28]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E.,
RA Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K.,
RA Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-
RT terminal acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [29]
RP X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS).
RX PubMed=8766818; DOI=10.1016/0014-5793(96)00553-4;
RA Sugimoto H., Suzuki M., Nakagawa A., Tanaka I., Nishihira J.;
RT "Crystal structure of macrophage migration inhibitory factor from
RT human lymphocyte at 2.1-A resolution.";
RL FEBS Lett. 389:145-148(1996).
RN [30]
RP X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS).
RX PubMed=8610159; DOI=10.1073/pnas.93.7.3007;
RA Kato Y., Muto T., Tomura T., Tsumura H., Watarai H., Mikayama T.,
RA Ishizaka K., Kuroki R.;
RT "The crystal structure of human glycosylation-inhibiting factor is a
RT trimeric barrel with three 6-stranded beta-sheets.";
RL Proc. Natl. Acad. Sci. U.S.A. 93:3007-3010(1996).
RN [31]
RP X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS).
RX PubMed=8643551; DOI=10.1073/pnas.93.11.5191;
RA Sun H.W., Bernhagen J., Bucala R., Lolis E.;
RT "Crystal structure at 2.6-A resolution of human macrophage migration
RT inhibitory factor.";
RL Proc. Natl. Acad. Sci. U.S.A. 93:5191-5196(1996).
RN [32]
RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS).
RX PubMed=10353846; DOI=10.1021/bi990306m;
RA Lubetsky J.B., Swope M., Dealwis C., Blake P., Lolis E.;
RT "Pro-1 of macrophage migration inhibitory factor functions as a
RT catalytic base in the phenylpyruvate tautomerase activity.";
RL Biochemistry 38:7346-7354(1999).
RN [33]
RP X-RAY CRYSTALLOGRAPHY (1.5 ANGSTROMS) IN COMPLEX WITH TAUTOMERASE
RP INHIBITOR, AND CATALYTIC ACTIVITY.
RX PubMed=11170644; DOI=10.1021/jm000386o;
RA Orita M., Yamamoto S., Katayama N., Aoki M., Takayama K., Yamagiwa Y.,
RA Seki N., Suzuki H., Kurihara H., Sakashita H., Takeuchi M., Fujita S.,
RA Yamada T., Tanaka A.;
RT "Coumarin and chromen-4-one analogues as tautomerase inhibitors of
RT macrophage migration inhibitory factor: discovery and X-ray
RT crystallography.";
RL J. Med. Chem. 44:540-547(2001).
RN [34]
RP X-RAY CRYSTALLOGRAPHY (1.75 ANGSTROMS) IN COMPLEX WITH
RP CARBONYLOXIME-BASED INHIBITORS, AND SUBUNIT.
RX PubMed=17526494; DOI=10.1074/jbc.M701825200;
RA Crichlow G.V., Cheng K.F., Dabideen D., Ochani M., Aljabari B.,
RA Pavlov V.A., Miller E.J., Lolis E., Al-Abed Y.;
RT "Alternative chemical modifications reverse the binding orientation of
RT a pharmacophore scaffold in the active site of macrophage migration
RT inhibitory factor.";
RL J. Biol. Chem. 282:23089-23095(2007).
RN [35]
RP X-RAY CRYSTALLOGRAPHY (1.55 ANGSTROMS) IN COMPLEX WITH THE INHIBITOR
RP N-ACETYL-P-BENZOQUINONE IMINE, SUBUNIT, AND CATALYTIC ACTIVITY.
RX PubMed=19090677; DOI=10.1021/bi8014423;
RA Crichlow G.V., Lubetsky J.B., Leng L., Bucala R., Lolis E.J.;
RT "Structural and kinetic analyses of macrophage migration inhibitory
RT factor active site interactions.";
RL Biochemistry 48:132-139(2009).
RN [36]
RP X-RAY CRYSTALLOGRAPHY (2.33 ANGSTROMS), FUNCTION, CATALYTIC ACTIVITY,
RP INTERACTION WITH CD74, MUTAGENESIS OF ASN-111, AND SUBUNIT.
RX PubMed=23776208; DOI=10.1073/pnas.1221817110;
RA Fan C., Rajasekaran D., Syed M.A., Leng L., Loria J.P., Bhandari V.,
RA Bucala R., Lolis E.J.;
RT "MIF intersubunit disulfide mutant antagonist supports activation of
RT CD74 by endogenous MIF trimer at physiologic concentrations.";
RL Proc. Natl. Acad. Sci. U.S.A. 110:10994-10999(2013).
CC -!- FUNCTION: Pro-inflammatory cytokine. Involved in the innate immune
CC response to bacterial pathogens. The expression of MIF at sites of
CC inflammation suggests a role as mediator in regulating the
CC function of macrophages in host defense. Counteracts the anti-
CC inflammatory activity of glucocorticoids. Has phenylpyruvate
CC tautomerase and dopachrome tautomerase activity (in vitro), but
CC the physiological substrate is not known. It is not clear whether
CC the tautomerase activity has any physiological relevance, and
CC whether it is important for cytokine activity.
CC -!- CATALYTIC ACTIVITY: Keto-phenylpyruvate = enol-phenylpyruvate.
CC -!- CATALYTIC ACTIVITY: L-dopachrome = 5,6-dihydroxyindole-2-
CC carboxylate.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=249 uM for phenylpyruvate;
CC KM=168 uM for p-hydroxyphenylpyruvate;
CC Vmax=2113 umol/min/mg enzyme toward phenylpyruvate;
CC Vmax=524 umol/min/mg enzyme toward p-hydroxyphenylpyruvate;
CC -!- SUBUNIT: Homotrimer. Interacts with CXCR2 extracellular domain (By
CC similarity). Interacts with the CD74 extracellular domain, COPS5
CC and BNIPL.
CC -!- INTERACTION:
CC O43521-2:BCL2L11; NbExp=5; IntAct=EBI-372712, EBI-526420;
CC -!- SUBCELLULAR LOCATION: Secreted. Cytoplasm. Note=Does not have a
CC cleavable signal sequence and is secreted via a specialized, non-
CC classical pathway. Secreted by macrophages upon stimulation by
CC bacterial lipopolysaccharide (LPS), or by M.tuberculosis antigens.
CC -!- INDUCTION: Up-regulated in concanavalin-A-treated lymphocytes. Up-
CC regulated in macrophages upon exposure to M.tuberculosis antigens.
CC -!- DISEASE: Rheumatoid arthritis systemic juvenile (RASJ)
CC [MIM:604302]: An inflammatory articular disorder with systemic-
CC onset beginning before the age of 16. It represents a subgroup of
CC juvenile arthritis associated with severe extraarticular features
CC and occasionally fatal complications. During active phases of the
CC disorder, patients display a typical daily spiking fever, an
CC evanescent macular rash, lymphadenopathy, hepatosplenomegaly,
CC serositis, myalgia and arthritis. Note=Disease susceptibility is
CC associated with variations affecting the gene represented in this
CC entry.
CC -!- MISCELLANEOUS: Serum levels of MIF are elevated in patients with
CC severe sepsis or septic shock. High levels of MIF are correlated
CC with low survival. Drugs that inhibit tautomerase activity protect
CC against death due to sepsis.
CC -!- SIMILARITY: Belongs to the MIF family.
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/mif/";
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/MIFID41365ch22q11.html";
CC -----------------------------------------------------------------------
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DR EMBL; M25639; AAA36315.1; -; mRNA.
DR EMBL; L10612; AAA35892.1; -; mRNA.
DR EMBL; Z23063; CAA80598.1; -; mRNA.
DR EMBL; L19686; AAA21814.1; -; Genomic_DNA.
DR EMBL; AF469046; AAL78635.1; -; mRNA.
DR EMBL; EF611126; ABQ95571.1; -; mRNA.
DR EMBL; CR456520; CAG30406.1; -; mRNA.
DR EMBL; AK311929; BAG34870.1; -; mRNA.
DR EMBL; CR407644; CAG28572.1; -; mRNA.
DR EMBL; CR541651; CAG46452.1; -; mRNA.
DR EMBL; BT007148; AAP35812.1; -; mRNA.
DR EMBL; DQ307455; ABB96245.1; -; Genomic_DNA.
DR EMBL; CH471095; EAW59620.1; -; Genomic_DNA.
DR EMBL; BC000447; AAH00447.1; -; mRNA.
DR EMBL; BC007676; AAH07676.1; -; mRNA.
DR EMBL; BC008914; AAH08914.1; -; mRNA.
DR EMBL; BC013976; AAH13976.1; -; mRNA.
DR EMBL; BC022414; AAH22414.1; -; mRNA.
DR EMBL; BC053376; AAH53376.1; -; mRNA.
DR EMBL; M95775; AAA36179.1; -; mRNA.
DR PIR; A48793; A48793.
DR RefSeq; NP_002406.1; NM_002415.1.
DR UniGene; Hs.407995; -.
DR PDB; 1CA7; X-ray; 2.50 A; A/B/C=2-115.
DR PDB; 1CGQ; X-ray; 2.00 A; A/B/C=3-115.
DR PDB; 1GCZ; X-ray; 1.90 A; A/B/C=2-115.
DR PDB; 1GD0; X-ray; 1.50 A; A/B/C=2-115.
DR PDB; 1GIF; X-ray; 1.90 A; A/B/C=1-115.
DR PDB; 1LJT; X-ray; 2.00 A; A/B/C=2-114.
DR PDB; 1MIF; X-ray; 2.60 A; A/B/C=1-115.
DR PDB; 1P1G; X-ray; 2.50 A; A/B/C=3-115.
DR PDB; 2OOH; X-ray; 1.85 A; A/B/C=2-115.
DR PDB; 2OOW; X-ray; 1.75 A; A/B/C=2-115.
DR PDB; 2OOZ; X-ray; 1.80 A; A/B/C=2-115.
DR PDB; 3B9S; X-ray; 1.80 A; A/B/C=2-115.
DR PDB; 3CE4; X-ray; 1.55 A; A/B/C=2-115.
DR PDB; 3DJH; X-ray; 1.25 A; A/B/C=2-115.
DR PDB; 3DJI; X-ray; 1.95 A; A/B/C/D/E/F=2-115.
DR PDB; 3HOF; X-ray; 1.90 A; A/B/C=1-115.
DR PDB; 3IJG; X-ray; 1.70 A; A/B/C=2-115.
DR PDB; 3IJJ; X-ray; 1.25 A; A/B/C=2-115.
DR PDB; 3JSF; X-ray; 1.93 A; A/B/C=2-115.
DR PDB; 3JSG; X-ray; 1.58 A; A/B/C=2-115.
DR PDB; 3JTU; X-ray; 1.86 A; A/B/C=2-115.
DR PDB; 3L5P; X-ray; 1.80 A; A/B/C=2-115.
DR PDB; 3L5R; X-ray; 1.94 A; A/B/C=2-115.
DR PDB; 3L5S; X-ray; 1.86 A; A/B/C=2-115.
DR PDB; 3L5T; X-ray; 1.86 A; A/B/C=2-115.
DR PDB; 3L5U; X-ray; 1.90 A; A/B/C=2-115.
DR PDB; 3L5V; X-ray; 1.70 A; A/B/C=2-115.
DR PDB; 3SMB; X-ray; 1.60 A; A/B/C=2-115.
DR PDB; 3SMC; X-ray; 1.80 A; A/B/C=2-115.
DR PDB; 3U18; X-ray; 1.90 A; A/B/C=2-115.
DR PDB; 4ETG; X-ray; 1.61 A; A/B/C=2-115.
DR PDB; 4EUI; X-ray; 1.70 A; A/B/C=2-115.
DR PDB; 4EVG; X-ray; 1.70 A; A/B/C=2-115.
DR PDB; 4F2K; X-ray; 1.53 A; A/B/C=2-115.
DR PDB; 4GRN; X-ray; 1.25 A; A/B/C=3-115.
DR PDB; 4GRO; X-ray; 2.00 A; A/B/C/D/E/F/G/H=3-115.
DR PDB; 4GRP; X-ray; 1.27 A; A/B/C=3-115.
DR PDB; 4GRQ; X-ray; 1.65 A; A/B/C=3-115.
DR PDB; 4GRR; X-ray; 1.47 A; A/B/C=3-115.
DR PDB; 4GRU; X-ray; 1.92 A; A/B/C=2-115.
DR PDB; 4GUM; X-ray; 2.33 A; A/B/C/D/E/F/G/H/I=2-115.
DR PDBsum; 1CA7; -.
DR PDBsum; 1CGQ; -.
DR PDBsum; 1GCZ; -.
DR PDBsum; 1GD0; -.
DR PDBsum; 1GIF; -.
DR PDBsum; 1LJT; -.
DR PDBsum; 1MIF; -.
DR PDBsum; 1P1G; -.
DR PDBsum; 2OOH; -.
DR PDBsum; 2OOW; -.
DR PDBsum; 2OOZ; -.
DR PDBsum; 3B9S; -.
DR PDBsum; 3CE4; -.
DR PDBsum; 3DJH; -.
DR PDBsum; 3DJI; -.
DR PDBsum; 3HOF; -.
DR PDBsum; 3IJG; -.
DR PDBsum; 3IJJ; -.
DR PDBsum; 3JSF; -.
DR PDBsum; 3JSG; -.
DR PDBsum; 3JTU; -.
DR PDBsum; 3L5P; -.
DR PDBsum; 3L5R; -.
DR PDBsum; 3L5S; -.
DR PDBsum; 3L5T; -.
DR PDBsum; 3L5U; -.
DR PDBsum; 3L5V; -.
DR PDBsum; 3SMB; -.
DR PDBsum; 3SMC; -.
DR PDBsum; 3U18; -.
DR PDBsum; 4ETG; -.
DR PDBsum; 4EUI; -.
DR PDBsum; 4EVG; -.
DR PDBsum; 4F2K; -.
DR PDBsum; 4GRN; -.
DR PDBsum; 4GRO; -.
DR PDBsum; 4GRP; -.
DR PDBsum; 4GRQ; -.
DR PDBsum; 4GRR; -.
DR PDBsum; 4GRU; -.
DR PDBsum; 4GUM; -.
DR ProteinModelPortal; P14174; -.
DR SMR; P14174; 2-115.
DR DIP; DIP-31137N; -.
DR IntAct; P14174; 17.
DR MINT; MINT-5000040; -.
DR STRING; 9606.ENSP00000215754; -.
DR BindingDB; P14174; -.
DR ChEMBL; CHEMBL2085; -.
DR PhosphoSite; P14174; -.
DR DMDM; 1170955; -.
DR SWISS-2DPAGE; P14174; -.
DR PaxDb; P14174; -.
DR PeptideAtlas; P14174; -.
DR PRIDE; P14174; -.
DR DNASU; 4282; -.
DR Ensembl; ENST00000215754; ENSP00000215754; ENSG00000240972.
DR GeneID; 4282; -.
DR KEGG; hsa:4282; -.
DR UCSC; uc002zyr.1; human.
DR CTD; 4282; -.
DR GeneCards; GC22P024236; -.
DR H-InvDB; HIX0041297; -.
DR HGNC; HGNC:7097; MIF.
DR HPA; CAB005284; -.
DR HPA; HPA003868; -.
DR MIM; 153620; gene.
DR MIM; 604302; phenotype.
DR neXtProt; NX_P14174; -.
DR Orphanet; 85414; Systemic-onset juvenile idiopathic arthritis.
DR PharmGKB; PA30819; -.
DR eggNOG; NOG08790; -.
DR HOGENOM; HOG000112325; -.
DR HOVERGEN; HBG003240; -.
DR InParanoid; P14174; -.
DR KO; K07253; -.
DR OMA; PDRIYIN; -.
DR OrthoDB; EOG7GXPDN; -.
DR PhylomeDB; P14174; -.
DR EvolutionaryTrace; P14174; -.
DR GeneWiki; Macrophage_migration_inhibitory_factor; -.
DR GenomeRNAi; 4282; -.
DR NextBio; 16845; -.
DR PRO; PR:P14174; -.
DR ArrayExpress; P14174; -.
DR Bgee; P14174; -.
DR CleanEx; HS_MIF; -.
DR Genevestigator; P14174; -.
DR GO; GO:0009986; C:cell surface; IDA:BHF-UCL.
DR GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0005576; C:extracellular region; IDA:UniProtKB.
DR GO; GO:0005615; C:extracellular space; IEA:UniProtKB-KW.
DR GO; GO:0042056; F:chemoattractant activity; IDA:BHF-UCL.
DR GO; GO:0005125; F:cytokine activity; IDA:UniProtKB.
DR GO; GO:0004167; F:dopachrome isomerase activity; IDA:UniProtKB.
DR GO; GO:0050178; F:phenylpyruvate tautomerase activity; IDA:MGI.
DR GO; GO:0007569; P:cell aging; IEA:Ensembl.
DR GO; GO:0008283; P:cell proliferation; IDA:UniProtKB.
DR GO; GO:0007166; P:cell surface receptor signaling pathway; IDA:UniProtKB.
DR GO; GO:0030330; P:DNA damage response, signal transduction by p53 class mediator; IEA:Ensembl.
DR GO; GO:0006954; P:inflammatory response; IEA:UniProtKB-KW.
DR GO; GO:0045087; P:innate immune response; IEA:UniProtKB-KW.
DR GO; GO:0043066; P:negative regulation of apoptotic process; IDA:UniProtKB.
DR GO; GO:0090344; P:negative regulation of cell aging; IDA:BHF-UCL.
DR GO; GO:0071157; P:negative regulation of cell cycle arrest; IDA:BHF-UCL.
DR GO; GO:0032269; P:negative regulation of cellular protein metabolic process; IEA:Ensembl.
DR GO; GO:0043518; P:negative regulation of DNA damage response, signal transduction by p53 class mediator; IDA:BHF-UCL.
DR GO; GO:0010629; P:negative regulation of gene expression; IDA:BHF-UCL.
DR GO; GO:1902166; P:negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator; IDA:BHF-UCL.
DR GO; GO:0002906; P:negative regulation of mature B cell apoptotic process; IEA:Ensembl.
DR GO; GO:0033033; P:negative regulation of myeloid cell apoptotic process; IEA:Ensembl.
DR GO; GO:0090238; P:positive regulation of arachidonic acid secretion; IEA:Ensembl.
DR GO; GO:0030890; P:positive regulation of B cell proliferation; IDA:BHF-UCL.
DR GO; GO:2000343; P:positive regulation of chemokine (C-X-C motif) ligand 2 production; IEA:Ensembl.
DR GO; GO:0050715; P:positive regulation of cytokine secretion; IDA:BHF-UCL.
DR GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; IDA:BHF-UCL.
DR GO; GO:0048146; P:positive regulation of fibroblast proliferation; IDA:BHF-UCL.
DR GO; GO:0031666; P:positive regulation of lipopolysaccharide-mediated signaling pathway; IEA:Ensembl.
DR GO; GO:0043406; P:positive regulation of MAP kinase activity; IEA:Ensembl.
DR GO; GO:0061081; P:positive regulation of myeloid leukocyte cytokine production involved in immune response; IEA:Ensembl.
DR GO; GO:0033138; P:positive regulation of peptidyl-serine phosphorylation; IDA:BHF-UCL.
DR GO; GO:0050731; P:positive regulation of peptidyl-tyrosine phosphorylation; IDA:BHF-UCL.
DR GO; GO:0061078; P:positive regulation of prostaglandin secretion involved in immune response; IEA:Ensembl.
DR GO; GO:0010739; P:positive regulation of protein kinase A signaling cascade; IDA:BHF-UCL.
DR GO; GO:0001516; P:prostaglandin biosynthetic process; IDA:UniProtKB.
DR GO; GO:0070207; P:protein homotrimerization; IPI:UniProtKB.
DR GO; GO:0043030; P:regulation of macrophage activation; NAS:UniProtKB.
DR InterPro; IPR001398; Macrophage_inhib_fac.
DR InterPro; IPR019829; Macrophage_inhib_fac_CS.
DR InterPro; IPR014347; Tautomerase/MIF_sf.
DR PANTHER; PTHR11954; PTHR11954; 1.
DR Pfam; PF01187; MIF; 1.
DR ProDom; PD004816; Macrophage_inhib_fac; 1.
DR SUPFAM; SSF55331; SSF55331; 1.
DR PROSITE; PS01158; MIF; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Complete proteome; Cytokine; Cytoplasm;
KW Direct protein sequencing; Immunity; Inflammatory response;
KW Innate immunity; Isomerase; Reference proteome; Secreted.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 115 Macrophage migration inhibitory factor.
FT /FTId=PRO_0000158062.
FT ACT_SITE 2 2 Proton acceptor; via imino nitrogen.
FT BINDING 33 33 Substrate.
FT BINDING 65 65 Substrate; via amide nitrogen.
FT BINDING 98 98 Substrate.
FT MOD_RES 78 78 N6-acetyllysine.
FT MUTAGEN 111 111 N->C: Causes formation of interchain
FT disulfide bonds with Cys-81 from another
FT subunit.
FT CONFLICT 57 59 CAL -> WAF (in Ref. 6; ABQ95571).
FT CONFLICT 67 67 K -> R (in Ref. 9; CAG46452).
FT CONFLICT 79 79 L -> Q (in Ref. 9; CAG46452).
FT CONFLICT 81 81 C -> F (in Ref. 6; ABQ95571).
FT CONFLICT 106 106 N -> S (in Ref. 1; AAA36315).
FT CONFLICT 113 113 T -> P (in Ref. 6; ABQ95571).
FT STRAND 3 10
FT HELIX 12 14
FT HELIX 19 31
FT HELIX 35 37
FT STRAND 39 43
FT STRAND 47 50
FT STRAND 58 66
FT HELIX 70 88
FT HELIX 92 94
FT STRAND 95 101
FT HELIX 104 106
FT STRAND 107 109
FT STRAND 112 114
SQ SEQUENCE 115 AA; 12476 MW; 56D51107C05286B2 CRC64;
MPMFIVNTNV PRASVPDGFL SELTQQLAQA TGKPPQYIAV HVVPDQLMAF GGSSEPCALC
SLHSIGKIGG AQNRSYSKLL CGLLAERLRI SPDRVYINYY DMNAANVGWN NSTFA
//
MIM
153620
*RECORD*
*FIELD* NO
153620
*FIELD* TI
*153620 MACROPHAGE MIGRATION INHIBITORY FACTOR; MIF
;;MMIF
*FIELD* TX
CLONING
Migration inhibitory factor for guinea pig macrophages was the first
read morelymphokine to be discovered (Bloom and Bennett, 1966; David, 1966).
Expression of MIF activity was found to correlate well with delayed
hypersensitivity and cellular immunity in humans. MIF activity could be
detected in the synovia of patients with rheumatoid arthritis. The
expression of MIF at sites of inflammation suggested a role for the
mediator in regulating the function of macrophages in host defense.
Weiser et al. (1989) isolated a cDNA encoding human macrophage migration
inhibitory factor.
By Northern blot analysis, Paralkar and Wistow (1994) demonstrated a
single size of MIF mRNA (about 800 nucleotides) in all human tissues
examined. In contrast to previous reports, they found no evidence for
multiple genes for MIF in the human genome.
GENE STRUCTURE
Paralkar and Wistow (1994) showed that the MIF gene is remarkably small;
it has 3 exons separated by introns of only 189 and 95 bp, and covers
less than 1 kb.
Kozak et al. (1995) found that the exon/intron structure of the mouse
Mif gene resembles that of the human gene. Bozza et al. (1995) found
that the mouse Mif gene spans less than 0.7 kb of chromosomal DNA and is
composed of 3 exons.
Esumi et al. (1998) presented evidence that the gene for D-dopachrome
tautomerase (DDT; 602750) in human and mouse is identical in exon
structure to MIF. Both genes have 2 introns that are located at
equivalent positions, relative to a 2-fold repeat in protein structure.
Although in similar positions, the introns are in different phases
relative to the open reading frame. Other members of this superfamily
exist in nematodes and a plant, and a related gene in C. elegans shares
an intron position with MIF and DDT. In addition to similarities in
structure, the genes for DDT and MIF are closely linked on human
chromosome 22 and mouse chromosome 10.
GENE FUNCTION
Bernhagen et al. (1993) identified MIF as a major secreted protein
released by anterior pituitary cells in culture and in vivo in response
to stimulation with bacterial lipopolysaccharide. They concluded that it
plays a central role in the toxic response to endotoxemia and possibly
septic shock.
Bucala (1996) reviewed studies that led to the discovery of a pituitary
mediator that appeared to act as the counter-regulatory hormone for
glucocorticoid action within the immune system. Isolated as a product of
murine anterior pituitary cells, this peptide was sequenced and found to
be the mouse homolog of MIF. MIF has the unique property of being
released from macrophages and T cells in response to physiologic
concentrations of glucocorticoids. The secretion of MIF is tightly
regulated and decreases at high, antiinflammatory steroid
concentrations. Once released, MIF 'overrides' or counter-regulates the
immunosuppressive effects of steroids on immune cell activation and
cytokine production. Bucala (1996) stated that because glucocorticoids
are an integral part of the host's global response to infection or
tissue invasion, the physiologic role of MIF is to act at an
inflammatory site or lymph node to counterbalance the profound
inhibitory effect of steroids on the immune response.
Using full-length MIF as bait in a yeast 2-hybrid screen of a brain cDNA
library, Kleemann et al. (2000) captured Jun activation domain-binding
protein (JAB1, or COPS5; 604850) as an interacting partner of MIF. By
coimmunoprecipitation and pull-down experiments, Kleemann et al. (2000)
confirmed the specific MIF-JAB1 association. Confocal microscopic
analysis demonstrated that the MIF-JAB1 complex is localized in the
cytosol near the peripheral plasma membrane, suggesting a potential
connection between MIF and the integrin signaling pathways. Luciferase
reporter and gel shift analyses showed that endogenous and exogenous MIF
inhibited JAB1-induced activator protein-1 (AP1; 165160) transcriptional
activity but did not interfere with nuclear factor kappa-B (NFKB;
164011) activity. Likewise, recombinant MIF inhibited JAB1-stimulated
and tumor necrosis factor (TNF; 191160)-induced JNK (601158) activity.
MIF also induced p27 (CDKN1B; 600778) expression and mirrored
CDKN1B-mediated growth arrest through inhibition of JAB1-dependent
degradation of CDKN1B. Mutation analysis indicated that a 16-residue MIF
peptide spanning amino acids 50 through 65, including cys60, strongly
competed with wildtype MIF for JAB1 binding. Kleemann et al. (2000)
suggested that signaling through MIF-JAB1 is independent of a potential
MIF receptor and noted that JAB1 is the only protein demonstrated to
interact with MIF.
From the parasitic nematode Brugia malayi, an etiologic agent of
lymphatic filariasis, Pastrana et al. (1998) cloned a cDNA encoding a
protein (BmMif) that is 42% identical to human MIF. MIF homologs were
also found in related filarial species. Functional analysis demonstrated
that both parasite- and human-derived MIF, when placed with cells,
inhibited random migration of monocytes/macrophages, but when placed
away from cells increased monocyte/macrophage migration. Pastrana et al.
(1998) concluded that filarial parasites produce cytokine homologs that
have the potential to modify the host immunologic environment, thus
affecting the ability of the parasite to survive in vivo.
Roger et al. (2001) showed that mouse macrophages transfected with
antisense Mif mRNA and macrophages from Mif -/- mice are hyporesponsive
to lipopolysaccharide (LPS) stimulation, but not stimulation by
gram-positive bacteria, as shown by reduced TNFA and IL6 (147620)
production. The Mif antisense-treated cells and macrophages from
Mif-deficient mice, expressed reduced Tlr4 (603030), but not Tlr2
(603028), mRNA and protein. EMSA and promoter analysis indicated that
deficient Mif expression impairs basal PU.1 (165170) transcription
factor activity of the mouse Tlr4 gene, resulting in reduced Tlr4
protein expression and responsiveness to LPS and gram-negative bacteria.
Roger et al. (2001) suggested that inhibition of MIF activity may
benefit people with gram-negative septic shock.
Amin et al. (2003) determined that MAPK (see MAPK1; 176948) and PI3K
(see PIK3CA; 171834) were critical for MMIF-dependent migration of human
dermal microvascular endothelial cells through basement membrane, but
Src (190090) and p38 kinase (600289) were nonessential. Recombinant MMIF
also induced time-dependent increases in phosphorylation of proteins
along the MAPK and PI3K signaling pathways.
Using immunofluorescence microscopy, Bernhagen et al. (2007) showed that
cells expressing MIF induced monocyte arrest through CXCR2 (IL8RB;
146928) and T-cell arrest through CXCR4 (162643), but not through CXCR1
(IL8RA; 146929) or CXCR3 (300574). Transwell analysis revealed that MIF
stimulated leukocyte chemotaxis through CXCR2 and CXCR4 and elicited
rapid integrin (e.g., ITGAL (153370)/ITGB2 (600065)) activation, as well
as calcium mobilization. Flow cytometry, fluorescence microscopy, and
pull-down analyses showed that MIF interacted with CXCR2 and CXCR4 and
colocalized with CD74 (142790). Monocyte arrest in atherosclerosis-prone
mice required Mif and Cxcr2, and inflammatory responses induced by Mif
in mice also relied on Cxcr2. Antibody-mediated blockade of Mif, but not
of the canonical ligands of Cxcr2 and Cxcr4, in Apoe (107741) -/- mice
on a high-fat diet with atherosclerosis led to plaque regression.
Bernhagen et al. (2007) proposed that targeting MIF in atherosclerotic
individuals may be a therapeutic option.
Arjona et al. (2007) showed that patients with acute West Nile virus
(WNV; see 610379) infection had increased levels of MIF in plasma and
cerebrospinal fluid. Studies in mice (see ANIMAL MODEL) showed that MIF
is involved in WNV pathogenesis and suggested that pharmacotherapeutic
approaches targeting MIF may be useful in treating WNV encephalitis.
Miller et al. (2008) showed that MIF, an upstream regulator of
inflammation, is released in the ischemic heart, where it stimulates
AMPK (see 602739) activation through CD74, promotes glucose uptake, and
protects the heart during ischemia-reperfusion injury. Germline deletion
of the Mif gene impairs ischemic AMPK signaling in the mouse heart.
Human fibroblasts with a low-activity MIF promoter polymorphism have
diminished MIF release and AMPK activation during hypoxia. Thus, MIF
modulates the activation of the cardioprotective AMPK pathway during
ischemia, functionally linking inflammation and metabolism in the heart.
Miller et al. (2008) anticipated that genetic variation in MIF
expression may influence the response of the human heart to ischemia by
the AMPK pathway, and that diagnostic MIF genotyping might predict risk
in patients with coronary artery disease.
MAPPING
By interspecific backcross analyses, Kozak et al. (1995) showed that the
mouse Mif gene maps to chromosome 10. They mapped 9 additional loci
containing related sequences, apparently all processed pseudogenes, to
mouse chromosomes 1, 2, 3, 7, 8, 9, 12, 17, and 19. Bozza et al. (1995)
likewise mapped the gene to mouse chromosome 10 (between Bcr and S100b,
which had been mapped to human chromosomes 22q11 and 21q22.3,
respectively). They analyzed several pseudogenes and mapped 3 of them to
mouse chromosomes 1, 9, and 17.
Kozak et al. (1995) determined that the human genome contains no MIF
pseudogenes. Budarf et al. (1997) performed somatic cell hybrid panel
PCR with human-specific primers to localize the gene to human chromosome
22q11.2. They also performed fluorescence in situ hybridization and
found unequivocal mapping of MIF to chromosome 22q. Kozak et al. (1995)
had mapped the human MIF gene to chromosome 19.
MOLECULAR GENETICS
Donn et al. (2001) identified a G-to-C transition at position -173 of
the MIF gene (153620.0001) and screened for this polymorphism in 117
patients with systemic juvenile rheumatoid arthritis (604302) and 172
unrelated healthy controls. They found that individuals possessing the
MIF-173C allele had an increased risk of the disease (p = 0.0005). Donn
et al. (2002) screened for the MIF-173C allele in a group of 88 patients
with juvenile rheumatoid arthritis of varying clinical phenotypes. They
confirmed the increased risk of susceptibility to juvenile rheumatoid
arthritis and also found that the increased risk was not limited to any
one clinical subgroup.
ANIMAL MODEL
Among its many biologic functions, MIF induces inflammation at the
interface between the immune system and the
hypothalamus-pituitary-adrenal stress axis. Koebernick et al. (2002)
showed that Mif-deficient knockout mice failed to control an infection
with wildtype Salmonella typhimurium. Various measures indicated that
MIF is a key mediator in the host response to this infection. MIF not
only promotes development of a protective Th1 response but ameliorates
disease by altering levels of reactive nitrogen intermediates and
corticosteroid hormones, which both exert immunosuppressive functions.
Wang et al. (2006) noted that increased levels of MIF, possibly derived
from eosinophils, has been observed in bronchoalveolar lavage fluid
(BALF) of asthmatic patients (Rossi et al., 1998). Wang et al. (2006)
compared Mif -/- mice with wildtype mice using a mouse model of
pulmonary inflammation. Mif -/- mice had significant reductions in serum
IgE and alveolar inflammatory cell recruitment, reduced serum and BALF
cytokines and chemokines, and impaired Cd4 (186940) T-cell activation.
Wildtype mice displayed increased Mif levels in BALF. The
antigen-induced airway inflammation phenotype could be restored in Mif
-/- mice by reconstitution with wildtype mast cells. Wang et al. (2006)
concluded that mast cell-derived MIF is essential for experimentally
induced airway allergic disease.
Arjona et al. (2007) found that blocking Mif action in mice either by
antibody, small molecule antagonist, or gene deletion increased
resistance to WNV lethality. PCR and confocal microscopy showed that
mice lacking Mif had lower viral load and brain inflammation, as well as
lower circulating Tnf, than wildtype mice. Injection of Evans blue dye
demonstrated that the blood-brain barrier remained intact in Mif -/-
mice, but not in wildtype mice, after WNV challenge. Arjona et al.
(2007) concluded that MIF is involved in WNV pathogenesis and that
pharmacotherapeutic approaches targeting MIF may be useful in treating
WNV encephalitis.
NOMENCLATURE
The symbol MIF is also used for mullerian inhibitory factor (600957),
but to avoid confusion, AMH, for anti-mullerian hormone, has been
declared the preferred symbol for the latter gene.
*FIELD* AV
.0001
RHEUMATOID ARTHRITIS, SYSTEMIC JUVENILE, SUSCEPTIBILITY TO
MIF, -173G-C
Donn et al. (2001) identified a G-to-C transition at position -173 of
the MIF gene and screened for this polymorphism in 117 patients with
systemic juvenile rheumatoid arthritis (604302) and 172 unrelated
healthy controls. They found that individuals possessing the MIF-173C
allele had an increased risk of the disease (p = 0.0005).
De Benedetti et al. (2003) studied 136 patients with systemic juvenile
rheumatoid arthritis and found that the MIF-173C allele was associated
with higher serum and synovial fluid levels of MIF, poorer response to
glucocorticoid treatment, persistence of active disease, and a poor
functional outcome.
*FIELD* RF
1. Amin, M. A.; Volpert, O. V.; Woods, J. M.; Kumar, P.; Harlow, L.
A.; Koch, A. E.: Migration inhibitory factor mediates angiogenesis
via mitogen-activated protein kinase and phosphatidylinositol kinase. Circ.
Res. 93: 321-329, 2003.
2. Arjona, A.; Foellmer, H. G.; Town, T.; Leng, L.; McDonald, C.;
Wang, T.; Wong, S. J.; Montgomery, R. R.; Fikrig, E.; Bucala, R.:
Abrogation of macrophage migration inhibitory factor decreases West
Nile virus lethality by limiting viral neuroinvasion. J. Clin. Invest. 117:
3059-3066, 2007.
3. Bernhagen, J.; Calandra, T.; Mitchell, R. A.; Martin, S. B.; Tracey,
K. J.; Voelter, W.; Manogue, K. R.; Cerami, A.; Bucala, R.: MIF is
a pituitary-derived cytokine that potentiates lethal endotoxaemia. Nature 365:
756-759, 1993. Note: Erratum: Nature 378: 419 only, 1995.
4. Bernhagen, J.; Krohn, R.; Lue, H.; Gregory, J. L.; Zernecke, A.;
Koenen, R. R.; Dewor, M.; Georgiev, I.; Schober, A.; Leng, L.; Kooistra,
T.; Fingerle-Rowson, G.; Ghezzi, P.; Kleemann, R.; McColl, S. R.;
Bucala, R.; Hickey, M. J.; Weber, C.: MIF is a noncognate ligand
of CXC chemokine receptors in inflammatory and atherogenic cell recruitment. Nature
Med. 13: 587-596, 2007.
5. Bloom, B. R.; Bennett, B.: Mechanism of a reaction in vitro associated
with delayed-type hypersensitivity. Science 153: 80-82, 1966.
6. Bozza, M.; Kolakowski, L. F., Jr.; Jenkins, N. A.; Gilbert, D.
J.; Copeland, N. G.; David, J. R.; Gerard, C.: Structural characterization
and chromosomal location of the mouse macrophage migration inhibitory
factor gene and pseudogenes. Genomics 27: 412-419, 1995.
7. Bucala, R.: MIF rediscovered: cytokine, pituitary hormone, and
glucocorticoid-induced regulator of the immune response. FASEB J. 10:
1607-1613, 1996.
8. Budarf, M.; McDonald, T.; Sellinger, B.; Kozak, C.; Graham, C.;
Wistow, G.: Localization of the human gene for macrophage migration
inhibitory factor (MIF) to chromosome 22q11.2. Genomics 39: 235-236,
1997.
9. David, J. R.: Delayed hypersensitivity in vitro: its mediation
by cell-free substances formed by lymphoid cell-antigen interaction. Proc.
Nat. Acad. Sci. 56: 72-77, 1966.
10. De Benedetti, F.; Meazza, C.; Vivarelli, M.; Rossi, F.; Pistorio,
A.; Lamb, R.; Lunt, M.; Thomson, W.; the British Paediatric Rheumatology
Study Group; Ravelli, A.; Donn, R.; Martini, A.: Functional and
prognostic relevance of the -173 polymorphism of the macrophage migration
inhibitory factor gene in systemic-onset juvenile idiopathic arthritis. Arthritis
Rheum. 48: 1398-1407, 2003.
11. Donn, R.; Alourfi, Z.; De Benedetti, F.; Meazza, C.; Zeggini,
E.; Lunt, M.; Stevens, A.; Shelley, E.; Lamb, R.; the British Paediatric
Rheumatology Study Group; Ollier, W. E. R.; Thomson, W.; Ray, D.
: Mutation screening of the macrophage migration inhibitory factor
gene: positive association of a functional polymorphism of macrophage
migration inhibitory factor with juvenile idiopathic arthritis. Arthritis
Rheum. 46: 2402-2409, 2002.
12. Donn, R. P.; Shelley, E.; Ollier, W. E. R.; Thomson, W.; the
British Paediatric Rheumatology Study Group: A novel 5-prime-flanking
region polymorphism of macrophage migration inhibitory factor is associated
with systemic-onset juvenile idiopathic arthritis. Arthritis Rheum. 44:
1782-1785, 2001.
13. Esumi, N.; Budarf, M.; Ciccarelli, L.; Sellinger, B.; Kozak, C.
A.; Wistow, G.: Conserved gene structure and genomic linkage for
D-dopachrome tautomerase (DDT) and MIF. Mammalian Genome 9: 753-757,
1998.
14. Kleemann, R.; Hausser, A.; Geiger, G.; Mischke, R.; Burger-Kentischer,
A.; Flieger, O.; Johannes, F.-J.; Roger, T.; Calandra, T.; Kapurniotu,
A.; Grell, M.; Finkelmeier, D.; Brunner, H.; Bernhagen, J.: Intracellular
action of the cytokine MIF to modulate AP-1 activity and the cell
cycle through Jab1. Nature 408: 211-216, 2000.
15. Koebernick, H.; Grode, L.; David, J. R.; Rohde, W.; Rolph, M.
S.; Mittrucker, H.-W.; Kaufmann, S. H. E.: Macrophage migration inhibitory
factor (MIF) plays a pivotal role in immunity against Salmonella typhimurium. Proc.
Nat. Acad. Sci. 99: 13681-13686, 2002.
16. Kozak, C. A.; Adamson, M. C.; Buckler, C. E.; Segovia, L.; Paralkar,
V.; Wistow, G.: Genomic cloning of mouse MIF (macrophage inhibitory
factor) and genetic mapping of the human and mouse expressed gene
and nine mouse pseudogenes. Genomics 27: 405-411, 1995.
17. Miller, E. J.; Li, J.; Leng, L.; McDonald, C.; Atsumi, T.; Bucala,
R.; Young, L. H.: Macrophage migration inhibitory factor stimulates
AMP-activated protein kinase in the ischaemic heart. Nature 451:
578-582, 2008.
18. Paralkar, V.; Wistow, G.: Cloning the human gene for macrophage
migration inhibitory factor (MIF). Genomics 19: 48-51, 1994.
19. Pastrana, D. V.; Raghavan, N.; Fitzgerald, P.; Eisinger, S. W.;
Metz, C.; Bucala, R.; Schleimer, R. P.; Bickel, C.; Scott, A. L.:
Filarial nematode parasites secrete a homologue of the human cytokine
macrophage migration inhibitory factor. Infect. Immun. 66: 5955-5963,
1998.
20. Roger, T.; David, J.; Glauser, M. P.; Calandra, T.: MIF regulates
innate immune response through modulation of Toll-like receptor 4. Nature 414:
920-924, 2001.
21. Rossi, A. G.; Haslett, C.; Hirani, N.; Greening, A. P.; Rahman,
I.; Metz, C. N.; Bucala, R.; Donnelly, S. C.: Human circulating eosinophils
secrete macrophage migration inhibitory factor (MIF): potential role
in asthma. J. Clin. Invest. 101: 2869-2874, 1998.
22. Wang, B.; Huang, X.; Wolters, P. J.; Sun, J.; Kitamoto, S.; Yang,
M.; Riese, R.; Leng, L.; Chapman, H. A.; Finn, P. W.; David, J. R.;
Bucala, R.; Shi, G.-P.: Cutting edge: deficiency of macrophage migration
inhibitory factor impairs murine airway allergic responses. J. Immun. 177:
5779-5784, 2006.
23. Weiser, W. Y.; Temple, P. A.; Witek-Giannotti, J. S.; Remold,
H. G.; Clark, S. C.; David, J. R.: Molecular cloning of a cDNA encoding
a human macrophage migration inhibitory factor. Proc. Nat. Acad.
Sci. 86: 7522-7526, 1989.
*FIELD* CN
Ada Hamosh - updated: 4/4/2008
Paul J. Converse - updated: 11/2/2007
Paul J. Converse - updated: 9/18/2007
Paul J. Converse - updated: 6/12/2007
Patricia A. Hartz - updated: 11/16/2004
Marla J. F. O'Neill - updated: 3/11/2004
Victor A. McKusick - updated: 11/21/2002
Paul J. Converse - updated: 12/19/2001
Paul J. Converse - updated: 11/7/2000
Victor A. McKusick - updated: 9/18/1998
Jennifer P. Macke - updated: 11/19/1997
Victor A. McKusick - updated: 4/4/1997
*FIELD* CD
Victor A. McKusick: 10/25/1989
*FIELD* ED
alopez: 04/30/2013
terry: 9/26/2008
alopez: 4/14/2008
terry: 4/4/2008
mgross: 11/5/2007
terry: 11/2/2007
mgross: 10/26/2007
terry: 9/18/2007
mgross: 6/12/2007
mgross: 11/16/2004
carol: 3/11/2004
cwells: 11/21/2002
terry: 11/20/2002
alopez: 12/19/2001
mgross: 11/7/2000
terry: 9/18/1998
alopez: 12/17/1997
alopez: 12/11/1997
alopez: 12/9/1997
jenny: 4/4/1997
terry: 4/1/1997
mark: 12/12/1995
mark: 7/30/1995
mimadm: 11/6/1994
carol: 2/7/1994
carol: 12/13/1993
carol: 12/6/1993
supermim: 3/16/1992
*RECORD*
*FIELD* NO
153620
*FIELD* TI
*153620 MACROPHAGE MIGRATION INHIBITORY FACTOR; MIF
;;MMIF
*FIELD* TX
CLONING
Migration inhibitory factor for guinea pig macrophages was the first
read morelymphokine to be discovered (Bloom and Bennett, 1966; David, 1966).
Expression of MIF activity was found to correlate well with delayed
hypersensitivity and cellular immunity in humans. MIF activity could be
detected in the synovia of patients with rheumatoid arthritis. The
expression of MIF at sites of inflammation suggested a role for the
mediator in regulating the function of macrophages in host defense.
Weiser et al. (1989) isolated a cDNA encoding human macrophage migration
inhibitory factor.
By Northern blot analysis, Paralkar and Wistow (1994) demonstrated a
single size of MIF mRNA (about 800 nucleotides) in all human tissues
examined. In contrast to previous reports, they found no evidence for
multiple genes for MIF in the human genome.
GENE STRUCTURE
Paralkar and Wistow (1994) showed that the MIF gene is remarkably small;
it has 3 exons separated by introns of only 189 and 95 bp, and covers
less than 1 kb.
Kozak et al. (1995) found that the exon/intron structure of the mouse
Mif gene resembles that of the human gene. Bozza et al. (1995) found
that the mouse Mif gene spans less than 0.7 kb of chromosomal DNA and is
composed of 3 exons.
Esumi et al. (1998) presented evidence that the gene for D-dopachrome
tautomerase (DDT; 602750) in human and mouse is identical in exon
structure to MIF. Both genes have 2 introns that are located at
equivalent positions, relative to a 2-fold repeat in protein structure.
Although in similar positions, the introns are in different phases
relative to the open reading frame. Other members of this superfamily
exist in nematodes and a plant, and a related gene in C. elegans shares
an intron position with MIF and DDT. In addition to similarities in
structure, the genes for DDT and MIF are closely linked on human
chromosome 22 and mouse chromosome 10.
GENE FUNCTION
Bernhagen et al. (1993) identified MIF as a major secreted protein
released by anterior pituitary cells in culture and in vivo in response
to stimulation with bacterial lipopolysaccharide. They concluded that it
plays a central role in the toxic response to endotoxemia and possibly
septic shock.
Bucala (1996) reviewed studies that led to the discovery of a pituitary
mediator that appeared to act as the counter-regulatory hormone for
glucocorticoid action within the immune system. Isolated as a product of
murine anterior pituitary cells, this peptide was sequenced and found to
be the mouse homolog of MIF. MIF has the unique property of being
released from macrophages and T cells in response to physiologic
concentrations of glucocorticoids. The secretion of MIF is tightly
regulated and decreases at high, antiinflammatory steroid
concentrations. Once released, MIF 'overrides' or counter-regulates the
immunosuppressive effects of steroids on immune cell activation and
cytokine production. Bucala (1996) stated that because glucocorticoids
are an integral part of the host's global response to infection or
tissue invasion, the physiologic role of MIF is to act at an
inflammatory site or lymph node to counterbalance the profound
inhibitory effect of steroids on the immune response.
Using full-length MIF as bait in a yeast 2-hybrid screen of a brain cDNA
library, Kleemann et al. (2000) captured Jun activation domain-binding
protein (JAB1, or COPS5; 604850) as an interacting partner of MIF. By
coimmunoprecipitation and pull-down experiments, Kleemann et al. (2000)
confirmed the specific MIF-JAB1 association. Confocal microscopic
analysis demonstrated that the MIF-JAB1 complex is localized in the
cytosol near the peripheral plasma membrane, suggesting a potential
connection between MIF and the integrin signaling pathways. Luciferase
reporter and gel shift analyses showed that endogenous and exogenous MIF
inhibited JAB1-induced activator protein-1 (AP1; 165160) transcriptional
activity but did not interfere with nuclear factor kappa-B (NFKB;
164011) activity. Likewise, recombinant MIF inhibited JAB1-stimulated
and tumor necrosis factor (TNF; 191160)-induced JNK (601158) activity.
MIF also induced p27 (CDKN1B; 600778) expression and mirrored
CDKN1B-mediated growth arrest through inhibition of JAB1-dependent
degradation of CDKN1B. Mutation analysis indicated that a 16-residue MIF
peptide spanning amino acids 50 through 65, including cys60, strongly
competed with wildtype MIF for JAB1 binding. Kleemann et al. (2000)
suggested that signaling through MIF-JAB1 is independent of a potential
MIF receptor and noted that JAB1 is the only protein demonstrated to
interact with MIF.
From the parasitic nematode Brugia malayi, an etiologic agent of
lymphatic filariasis, Pastrana et al. (1998) cloned a cDNA encoding a
protein (BmMif) that is 42% identical to human MIF. MIF homologs were
also found in related filarial species. Functional analysis demonstrated
that both parasite- and human-derived MIF, when placed with cells,
inhibited random migration of monocytes/macrophages, but when placed
away from cells increased monocyte/macrophage migration. Pastrana et al.
(1998) concluded that filarial parasites produce cytokine homologs that
have the potential to modify the host immunologic environment, thus
affecting the ability of the parasite to survive in vivo.
Roger et al. (2001) showed that mouse macrophages transfected with
antisense Mif mRNA and macrophages from Mif -/- mice are hyporesponsive
to lipopolysaccharide (LPS) stimulation, but not stimulation by
gram-positive bacteria, as shown by reduced TNFA and IL6 (147620)
production. The Mif antisense-treated cells and macrophages from
Mif-deficient mice, expressed reduced Tlr4 (603030), but not Tlr2
(603028), mRNA and protein. EMSA and promoter analysis indicated that
deficient Mif expression impairs basal PU.1 (165170) transcription
factor activity of the mouse Tlr4 gene, resulting in reduced Tlr4
protein expression and responsiveness to LPS and gram-negative bacteria.
Roger et al. (2001) suggested that inhibition of MIF activity may
benefit people with gram-negative septic shock.
Amin et al. (2003) determined that MAPK (see MAPK1; 176948) and PI3K
(see PIK3CA; 171834) were critical for MMIF-dependent migration of human
dermal microvascular endothelial cells through basement membrane, but
Src (190090) and p38 kinase (600289) were nonessential. Recombinant MMIF
also induced time-dependent increases in phosphorylation of proteins
along the MAPK and PI3K signaling pathways.
Using immunofluorescence microscopy, Bernhagen et al. (2007) showed that
cells expressing MIF induced monocyte arrest through CXCR2 (IL8RB;
146928) and T-cell arrest through CXCR4 (162643), but not through CXCR1
(IL8RA; 146929) or CXCR3 (300574). Transwell analysis revealed that MIF
stimulated leukocyte chemotaxis through CXCR2 and CXCR4 and elicited
rapid integrin (e.g., ITGAL (153370)/ITGB2 (600065)) activation, as well
as calcium mobilization. Flow cytometry, fluorescence microscopy, and
pull-down analyses showed that MIF interacted with CXCR2 and CXCR4 and
colocalized with CD74 (142790). Monocyte arrest in atherosclerosis-prone
mice required Mif and Cxcr2, and inflammatory responses induced by Mif
in mice also relied on Cxcr2. Antibody-mediated blockade of Mif, but not
of the canonical ligands of Cxcr2 and Cxcr4, in Apoe (107741) -/- mice
on a high-fat diet with atherosclerosis led to plaque regression.
Bernhagen et al. (2007) proposed that targeting MIF in atherosclerotic
individuals may be a therapeutic option.
Arjona et al. (2007) showed that patients with acute West Nile virus
(WNV; see 610379) infection had increased levels of MIF in plasma and
cerebrospinal fluid. Studies in mice (see ANIMAL MODEL) showed that MIF
is involved in WNV pathogenesis and suggested that pharmacotherapeutic
approaches targeting MIF may be useful in treating WNV encephalitis.
Miller et al. (2008) showed that MIF, an upstream regulator of
inflammation, is released in the ischemic heart, where it stimulates
AMPK (see 602739) activation through CD74, promotes glucose uptake, and
protects the heart during ischemia-reperfusion injury. Germline deletion
of the Mif gene impairs ischemic AMPK signaling in the mouse heart.
Human fibroblasts with a low-activity MIF promoter polymorphism have
diminished MIF release and AMPK activation during hypoxia. Thus, MIF
modulates the activation of the cardioprotective AMPK pathway during
ischemia, functionally linking inflammation and metabolism in the heart.
Miller et al. (2008) anticipated that genetic variation in MIF
expression may influence the response of the human heart to ischemia by
the AMPK pathway, and that diagnostic MIF genotyping might predict risk
in patients with coronary artery disease.
MAPPING
By interspecific backcross analyses, Kozak et al. (1995) showed that the
mouse Mif gene maps to chromosome 10. They mapped 9 additional loci
containing related sequences, apparently all processed pseudogenes, to
mouse chromosomes 1, 2, 3, 7, 8, 9, 12, 17, and 19. Bozza et al. (1995)
likewise mapped the gene to mouse chromosome 10 (between Bcr and S100b,
which had been mapped to human chromosomes 22q11 and 21q22.3,
respectively). They analyzed several pseudogenes and mapped 3 of them to
mouse chromosomes 1, 9, and 17.
Kozak et al. (1995) determined that the human genome contains no MIF
pseudogenes. Budarf et al. (1997) performed somatic cell hybrid panel
PCR with human-specific primers to localize the gene to human chromosome
22q11.2. They also performed fluorescence in situ hybridization and
found unequivocal mapping of MIF to chromosome 22q. Kozak et al. (1995)
had mapped the human MIF gene to chromosome 19.
MOLECULAR GENETICS
Donn et al. (2001) identified a G-to-C transition at position -173 of
the MIF gene (153620.0001) and screened for this polymorphism in 117
patients with systemic juvenile rheumatoid arthritis (604302) and 172
unrelated healthy controls. They found that individuals possessing the
MIF-173C allele had an increased risk of the disease (p = 0.0005). Donn
et al. (2002) screened for the MIF-173C allele in a group of 88 patients
with juvenile rheumatoid arthritis of varying clinical phenotypes. They
confirmed the increased risk of susceptibility to juvenile rheumatoid
arthritis and also found that the increased risk was not limited to any
one clinical subgroup.
ANIMAL MODEL
Among its many biologic functions, MIF induces inflammation at the
interface between the immune system and the
hypothalamus-pituitary-adrenal stress axis. Koebernick et al. (2002)
showed that Mif-deficient knockout mice failed to control an infection
with wildtype Salmonella typhimurium. Various measures indicated that
MIF is a key mediator in the host response to this infection. MIF not
only promotes development of a protective Th1 response but ameliorates
disease by altering levels of reactive nitrogen intermediates and
corticosteroid hormones, which both exert immunosuppressive functions.
Wang et al. (2006) noted that increased levels of MIF, possibly derived
from eosinophils, has been observed in bronchoalveolar lavage fluid
(BALF) of asthmatic patients (Rossi et al., 1998). Wang et al. (2006)
compared Mif -/- mice with wildtype mice using a mouse model of
pulmonary inflammation. Mif -/- mice had significant reductions in serum
IgE and alveolar inflammatory cell recruitment, reduced serum and BALF
cytokines and chemokines, and impaired Cd4 (186940) T-cell activation.
Wildtype mice displayed increased Mif levels in BALF. The
antigen-induced airway inflammation phenotype could be restored in Mif
-/- mice by reconstitution with wildtype mast cells. Wang et al. (2006)
concluded that mast cell-derived MIF is essential for experimentally
induced airway allergic disease.
Arjona et al. (2007) found that blocking Mif action in mice either by
antibody, small molecule antagonist, or gene deletion increased
resistance to WNV lethality. PCR and confocal microscopy showed that
mice lacking Mif had lower viral load and brain inflammation, as well as
lower circulating Tnf, than wildtype mice. Injection of Evans blue dye
demonstrated that the blood-brain barrier remained intact in Mif -/-
mice, but not in wildtype mice, after WNV challenge. Arjona et al.
(2007) concluded that MIF is involved in WNV pathogenesis and that
pharmacotherapeutic approaches targeting MIF may be useful in treating
WNV encephalitis.
NOMENCLATURE
The symbol MIF is also used for mullerian inhibitory factor (600957),
but to avoid confusion, AMH, for anti-mullerian hormone, has been
declared the preferred symbol for the latter gene.
*FIELD* AV
.0001
RHEUMATOID ARTHRITIS, SYSTEMIC JUVENILE, SUSCEPTIBILITY TO
MIF, -173G-C
Donn et al. (2001) identified a G-to-C transition at position -173 of
the MIF gene and screened for this polymorphism in 117 patients with
systemic juvenile rheumatoid arthritis (604302) and 172 unrelated
healthy controls. They found that individuals possessing the MIF-173C
allele had an increased risk of the disease (p = 0.0005).
De Benedetti et al. (2003) studied 136 patients with systemic juvenile
rheumatoid arthritis and found that the MIF-173C allele was associated
with higher serum and synovial fluid levels of MIF, poorer response to
glucocorticoid treatment, persistence of active disease, and a poor
functional outcome.
*FIELD* RF
1. Amin, M. A.; Volpert, O. V.; Woods, J. M.; Kumar, P.; Harlow, L.
A.; Koch, A. E.: Migration inhibitory factor mediates angiogenesis
via mitogen-activated protein kinase and phosphatidylinositol kinase. Circ.
Res. 93: 321-329, 2003.
2. Arjona, A.; Foellmer, H. G.; Town, T.; Leng, L.; McDonald, C.;
Wang, T.; Wong, S. J.; Montgomery, R. R.; Fikrig, E.; Bucala, R.:
Abrogation of macrophage migration inhibitory factor decreases West
Nile virus lethality by limiting viral neuroinvasion. J. Clin. Invest. 117:
3059-3066, 2007.
3. Bernhagen, J.; Calandra, T.; Mitchell, R. A.; Martin, S. B.; Tracey,
K. J.; Voelter, W.; Manogue, K. R.; Cerami, A.; Bucala, R.: MIF is
a pituitary-derived cytokine that potentiates lethal endotoxaemia. Nature 365:
756-759, 1993. Note: Erratum: Nature 378: 419 only, 1995.
4. Bernhagen, J.; Krohn, R.; Lue, H.; Gregory, J. L.; Zernecke, A.;
Koenen, R. R.; Dewor, M.; Georgiev, I.; Schober, A.; Leng, L.; Kooistra,
T.; Fingerle-Rowson, G.; Ghezzi, P.; Kleemann, R.; McColl, S. R.;
Bucala, R.; Hickey, M. J.; Weber, C.: MIF is a noncognate ligand
of CXC chemokine receptors in inflammatory and atherogenic cell recruitment. Nature
Med. 13: 587-596, 2007.
5. Bloom, B. R.; Bennett, B.: Mechanism of a reaction in vitro associated
with delayed-type hypersensitivity. Science 153: 80-82, 1966.
6. Bozza, M.; Kolakowski, L. F., Jr.; Jenkins, N. A.; Gilbert, D.
J.; Copeland, N. G.; David, J. R.; Gerard, C.: Structural characterization
and chromosomal location of the mouse macrophage migration inhibitory
factor gene and pseudogenes. Genomics 27: 412-419, 1995.
7. Bucala, R.: MIF rediscovered: cytokine, pituitary hormone, and
glucocorticoid-induced regulator of the immune response. FASEB J. 10:
1607-1613, 1996.
8. Budarf, M.; McDonald, T.; Sellinger, B.; Kozak, C.; Graham, C.;
Wistow, G.: Localization of the human gene for macrophage migration
inhibitory factor (MIF) to chromosome 22q11.2. Genomics 39: 235-236,
1997.
9. David, J. R.: Delayed hypersensitivity in vitro: its mediation
by cell-free substances formed by lymphoid cell-antigen interaction. Proc.
Nat. Acad. Sci. 56: 72-77, 1966.
10. De Benedetti, F.; Meazza, C.; Vivarelli, M.; Rossi, F.; Pistorio,
A.; Lamb, R.; Lunt, M.; Thomson, W.; the British Paediatric Rheumatology
Study Group; Ravelli, A.; Donn, R.; Martini, A.: Functional and
prognostic relevance of the -173 polymorphism of the macrophage migration
inhibitory factor gene in systemic-onset juvenile idiopathic arthritis. Arthritis
Rheum. 48: 1398-1407, 2003.
11. Donn, R.; Alourfi, Z.; De Benedetti, F.; Meazza, C.; Zeggini,
E.; Lunt, M.; Stevens, A.; Shelley, E.; Lamb, R.; the British Paediatric
Rheumatology Study Group; Ollier, W. E. R.; Thomson, W.; Ray, D.
: Mutation screening of the macrophage migration inhibitory factor
gene: positive association of a functional polymorphism of macrophage
migration inhibitory factor with juvenile idiopathic arthritis. Arthritis
Rheum. 46: 2402-2409, 2002.
12. Donn, R. P.; Shelley, E.; Ollier, W. E. R.; Thomson, W.; the
British Paediatric Rheumatology Study Group: A novel 5-prime-flanking
region polymorphism of macrophage migration inhibitory factor is associated
with systemic-onset juvenile idiopathic arthritis. Arthritis Rheum. 44:
1782-1785, 2001.
13. Esumi, N.; Budarf, M.; Ciccarelli, L.; Sellinger, B.; Kozak, C.
A.; Wistow, G.: Conserved gene structure and genomic linkage for
D-dopachrome tautomerase (DDT) and MIF. Mammalian Genome 9: 753-757,
1998.
14. Kleemann, R.; Hausser, A.; Geiger, G.; Mischke, R.; Burger-Kentischer,
A.; Flieger, O.; Johannes, F.-J.; Roger, T.; Calandra, T.; Kapurniotu,
A.; Grell, M.; Finkelmeier, D.; Brunner, H.; Bernhagen, J.: Intracellular
action of the cytokine MIF to modulate AP-1 activity and the cell
cycle through Jab1. Nature 408: 211-216, 2000.
15. Koebernick, H.; Grode, L.; David, J. R.; Rohde, W.; Rolph, M.
S.; Mittrucker, H.-W.; Kaufmann, S. H. E.: Macrophage migration inhibitory
factor (MIF) plays a pivotal role in immunity against Salmonella typhimurium. Proc.
Nat. Acad. Sci. 99: 13681-13686, 2002.
16. Kozak, C. A.; Adamson, M. C.; Buckler, C. E.; Segovia, L.; Paralkar,
V.; Wistow, G.: Genomic cloning of mouse MIF (macrophage inhibitory
factor) and genetic mapping of the human and mouse expressed gene
and nine mouse pseudogenes. Genomics 27: 405-411, 1995.
17. Miller, E. J.; Li, J.; Leng, L.; McDonald, C.; Atsumi, T.; Bucala,
R.; Young, L. H.: Macrophage migration inhibitory factor stimulates
AMP-activated protein kinase in the ischaemic heart. Nature 451:
578-582, 2008.
18. Paralkar, V.; Wistow, G.: Cloning the human gene for macrophage
migration inhibitory factor (MIF). Genomics 19: 48-51, 1994.
19. Pastrana, D. V.; Raghavan, N.; Fitzgerald, P.; Eisinger, S. W.;
Metz, C.; Bucala, R.; Schleimer, R. P.; Bickel, C.; Scott, A. L.:
Filarial nematode parasites secrete a homologue of the human cytokine
macrophage migration inhibitory factor. Infect. Immun. 66: 5955-5963,
1998.
20. Roger, T.; David, J.; Glauser, M. P.; Calandra, T.: MIF regulates
innate immune response through modulation of Toll-like receptor 4. Nature 414:
920-924, 2001.
21. Rossi, A. G.; Haslett, C.; Hirani, N.; Greening, A. P.; Rahman,
I.; Metz, C. N.; Bucala, R.; Donnelly, S. C.: Human circulating eosinophils
secrete macrophage migration inhibitory factor (MIF): potential role
in asthma. J. Clin. Invest. 101: 2869-2874, 1998.
22. Wang, B.; Huang, X.; Wolters, P. J.; Sun, J.; Kitamoto, S.; Yang,
M.; Riese, R.; Leng, L.; Chapman, H. A.; Finn, P. W.; David, J. R.;
Bucala, R.; Shi, G.-P.: Cutting edge: deficiency of macrophage migration
inhibitory factor impairs murine airway allergic responses. J. Immun. 177:
5779-5784, 2006.
23. Weiser, W. Y.; Temple, P. A.; Witek-Giannotti, J. S.; Remold,
H. G.; Clark, S. C.; David, J. R.: Molecular cloning of a cDNA encoding
a human macrophage migration inhibitory factor. Proc. Nat. Acad.
Sci. 86: 7522-7526, 1989.
*FIELD* CN
Ada Hamosh - updated: 4/4/2008
Paul J. Converse - updated: 11/2/2007
Paul J. Converse - updated: 9/18/2007
Paul J. Converse - updated: 6/12/2007
Patricia A. Hartz - updated: 11/16/2004
Marla J. F. O'Neill - updated: 3/11/2004
Victor A. McKusick - updated: 11/21/2002
Paul J. Converse - updated: 12/19/2001
Paul J. Converse - updated: 11/7/2000
Victor A. McKusick - updated: 9/18/1998
Jennifer P. Macke - updated: 11/19/1997
Victor A. McKusick - updated: 4/4/1997
*FIELD* CD
Victor A. McKusick: 10/25/1989
*FIELD* ED
alopez: 04/30/2013
terry: 9/26/2008
alopez: 4/14/2008
terry: 4/4/2008
mgross: 11/5/2007
terry: 11/2/2007
mgross: 10/26/2007
terry: 9/18/2007
mgross: 6/12/2007
mgross: 11/16/2004
carol: 3/11/2004
cwells: 11/21/2002
terry: 11/20/2002
alopez: 12/19/2001
mgross: 11/7/2000
terry: 9/18/1998
alopez: 12/17/1997
alopez: 12/11/1997
alopez: 12/9/1997
jenny: 4/4/1997
terry: 4/1/1997
mark: 12/12/1995
mark: 7/30/1995
mimadm: 11/6/1994
carol: 2/7/1994
carol: 12/13/1993
carol: 12/6/1993
supermim: 3/16/1992
MIM
604302
*RECORD*
*FIELD* NO
604302
*FIELD* TI
#604302 RHEUMATOID ARTHRITIS, SYSTEMIC JUVENILE
;;SYSTEMIC JUVENILE RHEUMATOID ARTHRITIS
read more*FIELD* TX
A number sign (#) is used with this entry because multiple factors
influence the susceptibility to systemic juvenile rheumatoid arthritis.
Polymorphisms in the IL6 (147620.0001) and in the MIF gene (153620.0001)
have been found to be associated with susceptibility to the disorder.
Glass and Giannini (1999) reviewed juvenile rheumatoid arthritis as a
complex genetic trait.
CLINICAL FEATURES
Systemic juvenile rheumatoid arthritis is a subset of juvenile chronic,
or idiopathic, arthritis, representing approximately 11% of patients
with this disease. The systemic-onset form represents a subgroup most
likely to be associated with severe, debilitating, extraarticular
features, and occasionally fatal complications. Despite medical
treatment, many children still experience early joint destruction,
necessitating surgical replacement. Moreover, up to 48% of these
patients still have active disease after 10 years (Wallace and Levinson,
1991).
Systemic juvenile rheumatoid arthritis is a clinically homogeneous
disease. During active phases of the disorder, patients display a
typical 'quotidian' (daily) spiking fever, an evanescent macular rash,
lymphadenopathy, hepatosplenomegaly, serositis, myalgia, and arthritis.
They are frequently anemic with markedly elevated neutrophil and
platelet counts; they have a high erythrocyte sedimentation rate,
C-reactive protein, and serum fibrinogen. The particularly unusual
feature of acute systemic juvenile rheumatoid arthritis is the unique
pattern of fever. Rooney et al. (1995) found that interleukin-6 (IL6;
147620) concentration rises significantly in conjunction with the fever
spike, and then falls in parallel with the return of body temperature to
normal.
Thorne et al. (2007) stated that uveitis is reported to occur in about
30% of patients with juvenile idiopathic arthritis (JIA) who are
antinuclear antibody-positive regardless of the type of arthritis
present. The uveitis in these patients is typically a chronic,
bilateral, nongranulomatous, and asymptomatic anterior uveitis. In a
retrospective analysis of 75 patients with JIA-associated uveitis,
Thorne et al. (2007) found that incident vision loss and complications
were common. Active inflammation during follow-up was associated with
increased risk of visual impairment, but use of immunosuppressive drugs
appeared to reduce the risk.
MOLECULAR GENETICS
Fishman et al. (1998) found a relationship between a polymorphism of IL6
(147620.0001) and systemic juvenile rheumatoid arthritis.
Donn et al. (2001) identified a G-to-C transition at position -173 of
the MIF gene (153620.0001) and screened for this polymorphism in 117
patients with systemic juvenile rheumatoid arthritis and 172 unrelated
healthy controls. They found that individuals possessing the MIF-173C
allele had an increased risk of the disease (p = 0.0005). Donn et al.
(2002) screened for the MIF-173C allele in a group of 88 patients with
juvenile rheumatoid arthritis of varying clinical phenotypes. They
confirmed the increased risk of susceptibility to juvenile rheumatoid
arthritis and also found that the increased risk was not limited to any
one clinical subgroup. De Benedetti et al. (2003) studied 136 patients
with systemic juvenile rheumatoid arthritis and found that the MIF-173C
allele was associated with higher serum and synovial fluid levels of
MIF, poorer response to glucocorticoid treatment, persistence of active
disease, and a poor functional outcome.
*FIELD* SA
Symmons et al. (1996)
*FIELD* RF
1. De Benedetti, F.; Meazza, C.; Vivarelli, M.; Rossi, F.; Pistorio,
A.; Lamb, R.; Lunt, M.; Thomson, W.; the British Paediatric Rheumatology
Study Group; Ravelli, A.; Donn, R.; Martini, A.: Functional and
prognostic relevance of the -173 polymorphism of the macrophage migration
inhibitory factor gene in systemic-onset juvenile idiopathic arthritis. Arthritis
Rheum. 48: 1398-1407, 2003.
2. Donn, R.; Alourfi, Z.; De Benedetti, F.; Meazza, C.; Zeggini, E.;
Lunt, M.; Stevens, A.; Shelley, E.; Lamb, R.; the British Paediatric
Rheumatology Study Group; Ollier, W. E. R.; Thomson, W.; Ray, D.
: Mutation screening of the macrophage migration inhibitory factor
gene: positive association of a functional polymorphism of macrophage
migration inhibitory factor with juvenile idiopathic arthritis. Arthritis
Rheum. 46: 2402-2409, 2002.
3. Donn, R. P.; Shelley, E.; Ollier, W. E. R.; Thomson, W.; the British
Paediatric Rheumatology Study Group: A novel 5-prime-flanking region
polymorphism of macrophage migration inhibitory factor is associated
with systemic-onset juvenile idiopathic arthritis. Arthritis Rheum. 44:
1782-1785, 2001.
4. Fishman, D.; Faulds, G.; Jeffery, R.; Mohamed-Ali, V.; Yudkin,
J. S.; Humphries, S.; Woo, P.: The effect of novel polymorphisms
in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma
IL-6 levels, and an association with systemic-onset juvenile chronic
arthritis. J. Clin. Invest. 102: 1369-1376, 1998.
5. Glass, D. N.; Giannini, E. H.: Juvenile rheumatoid arthritis as
a complex genetic trait. Arthritis Rheum. 42: 2261-2268, 1999.
6. Rooney, M.; David, J.; Symons, J.; Di Giovine, F.; Varsani, H.;
Woo, P.: Inflammatory cytokine responses in juvenile chronic arthritis. Brit.
J. Rheum. 34: 454-460, 1995.
7. Symmons, D. P.; Jones, M.; Osborne, J.; Sills, J.; Southwood, T.
R.; Woo, P.: Pediatric rheumatology in the United Kingdom: data from
the British Pediatric Rheumatology Group National Diagnostic Register. J.
Rheum. 23: 1975-1980, 1996.
8. Thorne, J. E.; Woreta, F.; Kedhar, S. R.; Dunn, J. P.; Jabs, D.
A.: Juvenile idiopathic arthritis-associated uveitis: incidence of
ocular complications and visual acuity loss. Am. J. Ophthal. 143:
840-846, 2007.
9. Wallace, C. A.; Levinson, J. E.: Juvenile rheumatoid arthritis:
outcome and treatment for the 1990s. Rheum. Dis. Clin. North Am. 17:
891-905, 1991.
*FIELD* CN
Jane Kelly - updated: 11/28/2007
Marla J. F. O'Neill - updated: 3/11/2004
*FIELD* CD
Victor A. McKusick: 11/17/1999
*FIELD* ED
carol: 11/28/2007
carol: 3/11/2004
alopez: 1/6/2003
carol: 2/1/2000
carol: 11/17/1999
*RECORD*
*FIELD* NO
604302
*FIELD* TI
#604302 RHEUMATOID ARTHRITIS, SYSTEMIC JUVENILE
;;SYSTEMIC JUVENILE RHEUMATOID ARTHRITIS
read more*FIELD* TX
A number sign (#) is used with this entry because multiple factors
influence the susceptibility to systemic juvenile rheumatoid arthritis.
Polymorphisms in the IL6 (147620.0001) and in the MIF gene (153620.0001)
have been found to be associated with susceptibility to the disorder.
Glass and Giannini (1999) reviewed juvenile rheumatoid arthritis as a
complex genetic trait.
CLINICAL FEATURES
Systemic juvenile rheumatoid arthritis is a subset of juvenile chronic,
or idiopathic, arthritis, representing approximately 11% of patients
with this disease. The systemic-onset form represents a subgroup most
likely to be associated with severe, debilitating, extraarticular
features, and occasionally fatal complications. Despite medical
treatment, many children still experience early joint destruction,
necessitating surgical replacement. Moreover, up to 48% of these
patients still have active disease after 10 years (Wallace and Levinson,
1991).
Systemic juvenile rheumatoid arthritis is a clinically homogeneous
disease. During active phases of the disorder, patients display a
typical 'quotidian' (daily) spiking fever, an evanescent macular rash,
lymphadenopathy, hepatosplenomegaly, serositis, myalgia, and arthritis.
They are frequently anemic with markedly elevated neutrophil and
platelet counts; they have a high erythrocyte sedimentation rate,
C-reactive protein, and serum fibrinogen. The particularly unusual
feature of acute systemic juvenile rheumatoid arthritis is the unique
pattern of fever. Rooney et al. (1995) found that interleukin-6 (IL6;
147620) concentration rises significantly in conjunction with the fever
spike, and then falls in parallel with the return of body temperature to
normal.
Thorne et al. (2007) stated that uveitis is reported to occur in about
30% of patients with juvenile idiopathic arthritis (JIA) who are
antinuclear antibody-positive regardless of the type of arthritis
present. The uveitis in these patients is typically a chronic,
bilateral, nongranulomatous, and asymptomatic anterior uveitis. In a
retrospective analysis of 75 patients with JIA-associated uveitis,
Thorne et al. (2007) found that incident vision loss and complications
were common. Active inflammation during follow-up was associated with
increased risk of visual impairment, but use of immunosuppressive drugs
appeared to reduce the risk.
MOLECULAR GENETICS
Fishman et al. (1998) found a relationship between a polymorphism of IL6
(147620.0001) and systemic juvenile rheumatoid arthritis.
Donn et al. (2001) identified a G-to-C transition at position -173 of
the MIF gene (153620.0001) and screened for this polymorphism in 117
patients with systemic juvenile rheumatoid arthritis and 172 unrelated
healthy controls. They found that individuals possessing the MIF-173C
allele had an increased risk of the disease (p = 0.0005). Donn et al.
(2002) screened for the MIF-173C allele in a group of 88 patients with
juvenile rheumatoid arthritis of varying clinical phenotypes. They
confirmed the increased risk of susceptibility to juvenile rheumatoid
arthritis and also found that the increased risk was not limited to any
one clinical subgroup. De Benedetti et al. (2003) studied 136 patients
with systemic juvenile rheumatoid arthritis and found that the MIF-173C
allele was associated with higher serum and synovial fluid levels of
MIF, poorer response to glucocorticoid treatment, persistence of active
disease, and a poor functional outcome.
*FIELD* SA
Symmons et al. (1996)
*FIELD* RF
1. De Benedetti, F.; Meazza, C.; Vivarelli, M.; Rossi, F.; Pistorio,
A.; Lamb, R.; Lunt, M.; Thomson, W.; the British Paediatric Rheumatology
Study Group; Ravelli, A.; Donn, R.; Martini, A.: Functional and
prognostic relevance of the -173 polymorphism of the macrophage migration
inhibitory factor gene in systemic-onset juvenile idiopathic arthritis. Arthritis
Rheum. 48: 1398-1407, 2003.
2. Donn, R.; Alourfi, Z.; De Benedetti, F.; Meazza, C.; Zeggini, E.;
Lunt, M.; Stevens, A.; Shelley, E.; Lamb, R.; the British Paediatric
Rheumatology Study Group; Ollier, W. E. R.; Thomson, W.; Ray, D.
: Mutation screening of the macrophage migration inhibitory factor
gene: positive association of a functional polymorphism of macrophage
migration inhibitory factor with juvenile idiopathic arthritis. Arthritis
Rheum. 46: 2402-2409, 2002.
3. Donn, R. P.; Shelley, E.; Ollier, W. E. R.; Thomson, W.; the British
Paediatric Rheumatology Study Group: A novel 5-prime-flanking region
polymorphism of macrophage migration inhibitory factor is associated
with systemic-onset juvenile idiopathic arthritis. Arthritis Rheum. 44:
1782-1785, 2001.
4. Fishman, D.; Faulds, G.; Jeffery, R.; Mohamed-Ali, V.; Yudkin,
J. S.; Humphries, S.; Woo, P.: The effect of novel polymorphisms
in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma
IL-6 levels, and an association with systemic-onset juvenile chronic
arthritis. J. Clin. Invest. 102: 1369-1376, 1998.
5. Glass, D. N.; Giannini, E. H.: Juvenile rheumatoid arthritis as
a complex genetic trait. Arthritis Rheum. 42: 2261-2268, 1999.
6. Rooney, M.; David, J.; Symons, J.; Di Giovine, F.; Varsani, H.;
Woo, P.: Inflammatory cytokine responses in juvenile chronic arthritis. Brit.
J. Rheum. 34: 454-460, 1995.
7. Symmons, D. P.; Jones, M.; Osborne, J.; Sills, J.; Southwood, T.
R.; Woo, P.: Pediatric rheumatology in the United Kingdom: data from
the British Pediatric Rheumatology Group National Diagnostic Register. J.
Rheum. 23: 1975-1980, 1996.
8. Thorne, J. E.; Woreta, F.; Kedhar, S. R.; Dunn, J. P.; Jabs, D.
A.: Juvenile idiopathic arthritis-associated uveitis: incidence of
ocular complications and visual acuity loss. Am. J. Ophthal. 143:
840-846, 2007.
9. Wallace, C. A.; Levinson, J. E.: Juvenile rheumatoid arthritis:
outcome and treatment for the 1990s. Rheum. Dis. Clin. North Am. 17:
891-905, 1991.
*FIELD* CN
Jane Kelly - updated: 11/28/2007
Marla J. F. O'Neill - updated: 3/11/2004
*FIELD* CD
Victor A. McKusick: 11/17/1999
*FIELD* ED
carol: 11/28/2007
carol: 3/11/2004
alopez: 1/6/2003
carol: 2/1/2000
carol: 11/17/1999