Full text data of IL18
IL18
(IGIF, IL1F4)
[Confidence: low (only semi-automatic identification from reviews)]
Interleukin-18; IL-18 (Iboctadekin; Interferon gamma-inducing factor; IFN-gamma-inducing factor; Interleukin-1 gamma; IL-1 gamma; Flags: Precursor)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Interleukin-18; IL-18 (Iboctadekin; Interferon gamma-inducing factor; IFN-gamma-inducing factor; Interleukin-1 gamma; IL-1 gamma; Flags: Precursor)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
Q14116
ID IL18_HUMAN Reviewed; 193 AA.
AC Q14116; O75599; Q6FGY3; Q6WWJ7;
DT 15-JUL-1998, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-NOV-1996, sequence version 1.
DT 22-JAN-2014, entry version 130.
DE RecName: Full=Interleukin-18;
DE Short=IL-18;
DE AltName: Full=Iboctadekin;
DE AltName: Full=Interferon gamma-inducing factor;
DE Short=IFN-gamma-inducing factor;
DE AltName: Full=Interleukin-1 gamma;
DE Short=IL-1 gamma;
DE Flags: Precursor;
GN Name=IL18; Synonyms=IGIF, IL1F4;
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] (ISOFORM 1).
RC TISSUE=Liver;
RX PubMed=8666798;
RA Ushio S., Namba M., Okura T., Hattori K., Nukada Y., Akita K.,
RA Tanabe F., Konishi K., Micallef M., Fujii M., Torigoe K., Tanimoto T.,
RA Fukuda S., Ikeda M., Okamura H., Kurimoto M.;
RT "Cloning of the cDNA for human IFN-gamma-inducing factor, expression
RT in Escherichia coli, and studies on the biologic activities of the
RT protein.";
RL J. Immunol. 156:4274-4279(1996).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), PROTEOLYTIC PROCESSING, AND
RP ALTERNATIVE SPLICING.
RX PubMed=15326478; DOI=10.1038/sj.onc.1208036;
RA Gaggero A., De Ambrosis A., Mezzanzanica D., Piazza T., Rubartelli A.,
RA Figini M., Canevari S., Ferrini S.;
RT "A novel isoform of pro-interleukin-18 expressed in ovarian tumors is
RT resistant to caspase-1 and -4 processing.";
RL Oncogene 23:7552-7560(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RA Yong D., Guixin D., Lihua H., Haitao W.;
RT "Cloning and sequencing of the cDNA for precursor hIL-18.";
RL Submitted (JUL-1998) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RA Liu J., Peng X., Yuan J., Qiang B.;
RT "Cloning of human interleukin 18 cDNA.";
RL Submitted (JUL-2001) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
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 (JUN-2004) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16554811; DOI=10.1038/nature04632;
RA Taylor T.D., Noguchi H., Totoki Y., Toyoda A., Kuroki Y., Dewar K.,
RA Lloyd C., Itoh T., Takeda T., Kim D.-W., She X., Barlow K.F.,
RA Bloom T., Bruford E., Chang J.L., Cuomo C.A., Eichler E.,
RA FitzGerald M.G., Jaffe D.B., LaButti K., Nicol R., Park H.-S.,
RA Seaman C., Sougnez C., Yang X., Zimmer A.R., Zody M.C., Birren B.W.,
RA Nusbaum C., Fujiyama A., Hattori M., Rogers J., Lander E.S.,
RA Sakaki Y.;
RT "Human chromosome 11 DNA sequence and analysis including novel gene
RT identification.";
RL Nature 440:497-500(2006).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton 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 [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Urinary bladder;
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 [9]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 2-193 (ISOFORM 1).
RC TISSUE=Peripheral blood;
RA Conti B., Kim S.J., Tinti C., Chun H.S., Joh T.H.;
RL Submitted (FEB-1997) to the EMBL/GenBank/DDBJ databases.
RN [10]
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).
CC -!- FUNCTION: Augments natural killer cell activity in spleen cells
CC and stimulates interferon gamma production in T-helper type I
CC cells.
CC -!- SUBCELLULAR LOCATION: Secreted.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q14116-1; Sequence=Displayed;
CC Name=2; Synonyms=Delta3pro-IL-18;
CC IsoId=Q14116-2; Sequence=VSP_044934;
CC Note=Expressed in ovarian carcinoma but undetectable in normal
CC ovarian epithelial cells. Resistant to proteolytic activation by
CC caspase-1 and -4;
CC -!- PTM: The pro-IL-18 precursor is processed by CASP1 or CASP4 to
CC yield the active form.
CC -!- SIMILARITY: Belongs to the IL-1 family.
CC -!- WEB RESOURCE: Name=Wikipedia; Note=Interleukin-1 entry;
CC URL="http://en.wikipedia.org/wiki/Interleukin_1";
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; D49950; BAA08706.1; -; mRNA.
DR EMBL; AY266351; AAP92112.1; -; mRNA.
DR EMBL; AF077611; AAC27787.1; -; mRNA.
DR EMBL; AY044641; AAK95950.1; -; mRNA.
DR EMBL; CR541973; CAG46771.1; -; mRNA.
DR EMBL; CR542001; CAG46798.1; -; mRNA.
DR EMBL; AP002007; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AP002884; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471065; EAW67184.1; -; Genomic_DNA.
DR EMBL; BC007007; AAH07007.1; -; mRNA.
DR EMBL; BC007461; AAH07461.1; -; mRNA.
DR EMBL; U90434; AAB50010.1; -; mRNA.
DR RefSeq; NP_001230140.1; NM_001243211.1.
DR RefSeq; NP_001553.1; NM_001562.3.
DR UniGene; Hs.83077; -.
DR PDB; 1J0S; NMR; -; A=37-193.
DR PDB; 2VXT; X-ray; 1.49 A; I=37-193.
DR PDB; 3F62; X-ray; 2.00 A; B=37-193.
DR PDB; 4EEE; X-ray; 2.71 A; B/D=37-193.
DR PDB; 4EKX; X-ray; 1.75 A; B/D=37-193.
DR PDB; 4HJJ; X-ray; 2.10 A; A=37-192.
DR PDBsum; 1J0S; -.
DR PDBsum; 2VXT; -.
DR PDBsum; 3F62; -.
DR PDBsum; 4EEE; -.
DR PDBsum; 4EKX; -.
DR PDBsum; 4HJJ; -.
DR ProteinModelPortal; Q14116; -.
DR SMR; Q14116; 37-193.
DR DIP; DIP-3785N; -.
DR IntAct; Q14116; 1.
DR STRING; 9606.ENSP00000280357; -.
DR PhosphoSite; Q14116; -.
DR DMDM; 3219817; -.
DR OGP; Q14116; -.
DR PaxDb; Q14116; -.
DR PRIDE; Q14116; -.
DR DNASU; 3606; -.
DR Ensembl; ENST00000280357; ENSP00000280357; ENSG00000150782.
DR Ensembl; ENST00000524595; ENSP00000434561; ENSG00000150782.
DR Ensembl; ENST00000528832; ENSP00000434161; ENSG00000150782.
DR GeneID; 3606; -.
DR KEGG; hsa:3606; -.
DR UCSC; uc001pna.2; human.
DR CTD; 3606; -.
DR GeneCards; GC11M112013; -.
DR HGNC; HGNC:5986; IL18.
DR HPA; CAB007772; -.
DR HPA; CAB027385; -.
DR HPA; HPA003980; -.
DR MIM; 600953; gene.
DR neXtProt; NX_Q14116; -.
DR PharmGKB; PA29802; -.
DR eggNOG; NOG77229; -.
DR HOGENOM; HOG000048723; -.
DR HOVERGEN; HBG000388; -.
DR InParanoid; Q14116; -.
DR KO; K05482; -.
DR OMA; VPGHDDK; -.
DR OrthoDB; EOG7SR4NN; -.
DR Reactome; REACT_6900; Immune System.
DR EvolutionaryTrace; Q14116; -.
DR GeneWiki; Interleukin_18; -.
DR GenomeRNAi; 3606; -.
DR NextBio; 14093; -.
DR PMAP-CutDB; Q14116; -.
DR PRO; PR:Q14116; -.
DR ArrayExpress; Q14116; -.
DR Bgee; Q14116; -.
DR CleanEx; HS_IL18; -.
DR Genevestigator; Q14116; -.
DR GO; GO:0016324; C:apical plasma membrane; IEA:Ensembl.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005576; C:extracellular region; TAS:UniProtKB.
DR GO; GO:0005615; C:extracellular space; IEA:UniProtKB-KW.
DR GO; GO:0005125; F:cytokine activity; TAS:UniProtKB.
DR GO; GO:0001525; P:angiogenesis; IDA:UniProtKB.
DR GO; GO:0007267; P:cell-cell signaling; TAS:ProtInc.
DR GO; GO:0071320; P:cellular response to cAMP; IEA:Ensembl.
DR GO; GO:0070301; P:cellular response to hydrogen peroxide; IEA:Ensembl.
DR GO; GO:0071346; P:cellular response to interferon-gamma; IEA:Ensembl.
DR GO; GO:0071260; P:cellular response to mechanical stimulus; IEA:Ensembl.
DR GO; GO:0071407; P:cellular response to organic cyclic compound; IDA:UniProtKB.
DR GO; GO:0071374; P:cellular response to parathyroid hormone stimulus; IEA:Ensembl.
DR GO; GO:0071375; P:cellular response to peptide hormone stimulus; IEA:Ensembl.
DR GO; GO:0071356; P:cellular response to tumor necrosis factor; IEA:Ensembl.
DR GO; GO:0042033; P:chemokine biosynthetic process; TAS:UniProtKB.
DR GO; GO:0050966; P:detection of mechanical stimulus involved in sensory perception of pain; IEA:Ensembl.
DR GO; GO:0048546; P:digestive tract morphogenesis; IEA:Ensembl.
DR GO; GO:0042253; P:granulocyte macrophage colony-stimulating factor biosynthetic process; TAS:UniProtKB.
DR GO; GO:0006954; P:inflammatory response; IDA:UniProtKB.
DR GO; GO:0042095; P:interferon-gamma biosynthetic process; TAS:UniProtKB.
DR GO; GO:0042231; P:interleukin-13 biosynthetic process; TAS:UniProtKB.
DR GO; GO:0042094; P:interleukin-2 biosynthetic process; TAS:UniProtKB.
DR GO; GO:0031663; P:lipopolysaccharide-mediated signaling pathway; IDA:UniProtKB.
DR GO; GO:0030324; P:lung development; IEA:Ensembl.
DR GO; GO:0000165; P:MAPK cascade; IMP:UniProtKB.
DR GO; GO:0030101; P:natural killer cell activation; IEA:Ensembl.
DR GO; GO:0001649; P:osteoblast differentiation; IEA:Ensembl.
DR GO; GO:0042104; P:positive regulation of activated T cell proliferation; IDA:UniProtKB.
DR GO; GO:2000504; P:positive regulation of blood vessel remodeling; IEA:Ensembl.
DR GO; GO:0032722; P:positive regulation of chemokine production; IEA:Ensembl.
DR GO; GO:0032967; P:positive regulation of collagen biosynthetic process; IEA:Ensembl.
DR GO; GO:0010628; P:positive regulation of gene expression; IEA:Ensembl.
DR GO; GO:0032725; P:positive regulation of granulocyte macrophage colony-stimulating factor production; IDA:BHF-UCL.
DR GO; GO:0050729; P:positive regulation of inflammatory response; IC:BHF-UCL.
DR GO; GO:0032729; P:positive regulation of interferon-gamma production; IDA:BHF-UCL.
DR GO; GO:0032731; P:positive regulation of interleukin-1 beta production; IEA:Ensembl.
DR GO; GO:0032740; P:positive regulation of interleukin-17 production; IDA:BHF-UCL.
DR GO; GO:0032757; P:positive regulation of interleukin-8 production; IEA:Ensembl.
DR GO; GO:2000256; P:positive regulation of male germ cell proliferation; IEA:Ensembl.
DR GO; GO:0032819; P:positive regulation of natural killer cell proliferation; IDA:BHF-UCL.
DR GO; GO:0043525; P:positive regulation of neuron apoptotic process; IEA:Ensembl.
DR GO; GO:0042346; P:positive regulation of NF-kappaB import into nucleus; IEA:Ensembl.
DR GO; GO:0051142; P:positive regulation of NK T cell proliferation; IDA:BHF-UCL.
DR GO; GO:0032930; P:positive regulation of superoxide anion generation; IEA:Ensembl.
DR GO; GO:0034105; P:positive regulation of tissue remodeling; IC:BHF-UCL.
DR GO; GO:0032760; P:positive regulation of tumor necrosis factor production; IEA:Ensembl.
DR GO; GO:0043117; P:positive regulation of vascular permeability; IEA:Ensembl.
DR GO; GO:0030155; P:regulation of cell adhesion; IDA:UniProtKB.
DR GO; GO:0009409; P:response to cold; IEA:Ensembl.
DR GO; GO:0055093; P:response to hyperoxia; IEA:Ensembl.
DR GO; GO:0001666; P:response to hypoxia; IEA:Ensembl.
DR GO; GO:0009314; P:response to radiation; IEA:Ensembl.
DR GO; GO:0030431; P:sleep; ISS:UniProtKB.
DR GO; GO:0042088; P:T-helper 1 type immune response; IDA:UniProtKB.
DR GO; GO:0042092; P:type 2 immune response; TAS:UniProtKB.
DR InterPro; IPR008996; Cytokine_IL1-like.
DR InterPro; IPR000975; IL-1.
DR InterPro; IPR015529; IL-18.
DR PANTHER; PTHR11326; PTHR11326; 1.
DR Pfam; PF00340; IL1; 1.
DR PIRSF; PIRSF015162; Interleukin_18; 1.
DR PRINTS; PR01933; INTRLEUKIN18.
DR SMART; SM00125; IL1; 1.
DR SUPFAM; SSF50353; SSF50353; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Complete proteome; Cytokine;
KW Reference proteome; Secreted.
FT PROPEP 1 36 By similarity.
FT /FTId=PRO_0000015343.
FT CHAIN 37 193 Interleukin-18.
FT /FTId=PRO_0000015344.
FT VAR_SEQ 27 30 Missing (in isoform 2).
FT /FTId=VSP_044934.
FT CONFLICT 66 66 F -> L (in Ref. 3; AAC27787).
FT CONFLICT 86 86 S -> R (in Ref. 3; AAC27787).
FT CONFLICT 191 191 N -> S (in Ref. 3; AAC27787).
FT STRAND 42 49
FT STRAND 55 58
FT STRAND 64 67
FT HELIX 71 76
FT TURN 77 81
FT STRAND 83 91
FT TURN 92 94
FT STRAND 95 111
FT HELIX 113 115
FT STRAND 118 121
FT STRAND 126 131
FT STRAND 137 142
FT STRAND 145 156
FT STRAND 159 166
FT STRAND 169 176
FT TURN 178 180
FT HELIX 183 185
FT STRAND 187 191
SQ SEQUENCE 193 AA; 22326 MW; 323C62C203788D55 CRC64;
MAAEPVEDNC INFVAMKFID NTLYFIAEDD ENLESDYFGK LESKLSVIRN LNDQVLFIDQ
GNRPLFEDMT DSDCRDNAPR TIFIISMYKD SQPRGMAVTI SVKCEKISTL SCENKIISFK
EMNPPDNIKD TKSDIIFFQR SVPGHDNKMQ FESSSYEGYF LACEKERDLF KLILKKEDEL
GDRSIMFTVQ NED
//
ID IL18_HUMAN Reviewed; 193 AA.
AC Q14116; O75599; Q6FGY3; Q6WWJ7;
DT 15-JUL-1998, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-NOV-1996, sequence version 1.
DT 22-JAN-2014, entry version 130.
DE RecName: Full=Interleukin-18;
DE Short=IL-18;
DE AltName: Full=Iboctadekin;
DE AltName: Full=Interferon gamma-inducing factor;
DE Short=IFN-gamma-inducing factor;
DE AltName: Full=Interleukin-1 gamma;
DE Short=IL-1 gamma;
DE Flags: Precursor;
GN Name=IL18; Synonyms=IGIF, IL1F4;
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] (ISOFORM 1).
RC TISSUE=Liver;
RX PubMed=8666798;
RA Ushio S., Namba M., Okura T., Hattori K., Nukada Y., Akita K.,
RA Tanabe F., Konishi K., Micallef M., Fujii M., Torigoe K., Tanimoto T.,
RA Fukuda S., Ikeda M., Okamura H., Kurimoto M.;
RT "Cloning of the cDNA for human IFN-gamma-inducing factor, expression
RT in Escherichia coli, and studies on the biologic activities of the
RT protein.";
RL J. Immunol. 156:4274-4279(1996).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), PROTEOLYTIC PROCESSING, AND
RP ALTERNATIVE SPLICING.
RX PubMed=15326478; DOI=10.1038/sj.onc.1208036;
RA Gaggero A., De Ambrosis A., Mezzanzanica D., Piazza T., Rubartelli A.,
RA Figini M., Canevari S., Ferrini S.;
RT "A novel isoform of pro-interleukin-18 expressed in ovarian tumors is
RT resistant to caspase-1 and -4 processing.";
RL Oncogene 23:7552-7560(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RA Yong D., Guixin D., Lihua H., Haitao W.;
RT "Cloning and sequencing of the cDNA for precursor hIL-18.";
RL Submitted (JUL-1998) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RA Liu J., Peng X., Yuan J., Qiang B.;
RT "Cloning of human interleukin 18 cDNA.";
RL Submitted (JUL-2001) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
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 (JUN-2004) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16554811; DOI=10.1038/nature04632;
RA Taylor T.D., Noguchi H., Totoki Y., Toyoda A., Kuroki Y., Dewar K.,
RA Lloyd C., Itoh T., Takeda T., Kim D.-W., She X., Barlow K.F.,
RA Bloom T., Bruford E., Chang J.L., Cuomo C.A., Eichler E.,
RA FitzGerald M.G., Jaffe D.B., LaButti K., Nicol R., Park H.-S.,
RA Seaman C., Sougnez C., Yang X., Zimmer A.R., Zody M.C., Birren B.W.,
RA Nusbaum C., Fujiyama A., Hattori M., Rogers J., Lander E.S.,
RA Sakaki Y.;
RT "Human chromosome 11 DNA sequence and analysis including novel gene
RT identification.";
RL Nature 440:497-500(2006).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton 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 [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Urinary bladder;
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 [9]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 2-193 (ISOFORM 1).
RC TISSUE=Peripheral blood;
RA Conti B., Kim S.J., Tinti C., Chun H.S., Joh T.H.;
RL Submitted (FEB-1997) to the EMBL/GenBank/DDBJ databases.
RN [10]
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).
CC -!- FUNCTION: Augments natural killer cell activity in spleen cells
CC and stimulates interferon gamma production in T-helper type I
CC cells.
CC -!- SUBCELLULAR LOCATION: Secreted.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q14116-1; Sequence=Displayed;
CC Name=2; Synonyms=Delta3pro-IL-18;
CC IsoId=Q14116-2; Sequence=VSP_044934;
CC Note=Expressed in ovarian carcinoma but undetectable in normal
CC ovarian epithelial cells. Resistant to proteolytic activation by
CC caspase-1 and -4;
CC -!- PTM: The pro-IL-18 precursor is processed by CASP1 or CASP4 to
CC yield the active form.
CC -!- SIMILARITY: Belongs to the IL-1 family.
CC -!- WEB RESOURCE: Name=Wikipedia; Note=Interleukin-1 entry;
CC URL="http://en.wikipedia.org/wiki/Interleukin_1";
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; D49950; BAA08706.1; -; mRNA.
DR EMBL; AY266351; AAP92112.1; -; mRNA.
DR EMBL; AF077611; AAC27787.1; -; mRNA.
DR EMBL; AY044641; AAK95950.1; -; mRNA.
DR EMBL; CR541973; CAG46771.1; -; mRNA.
DR EMBL; CR542001; CAG46798.1; -; mRNA.
DR EMBL; AP002007; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AP002884; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471065; EAW67184.1; -; Genomic_DNA.
DR EMBL; BC007007; AAH07007.1; -; mRNA.
DR EMBL; BC007461; AAH07461.1; -; mRNA.
DR EMBL; U90434; AAB50010.1; -; mRNA.
DR RefSeq; NP_001230140.1; NM_001243211.1.
DR RefSeq; NP_001553.1; NM_001562.3.
DR UniGene; Hs.83077; -.
DR PDB; 1J0S; NMR; -; A=37-193.
DR PDB; 2VXT; X-ray; 1.49 A; I=37-193.
DR PDB; 3F62; X-ray; 2.00 A; B=37-193.
DR PDB; 4EEE; X-ray; 2.71 A; B/D=37-193.
DR PDB; 4EKX; X-ray; 1.75 A; B/D=37-193.
DR PDB; 4HJJ; X-ray; 2.10 A; A=37-192.
DR PDBsum; 1J0S; -.
DR PDBsum; 2VXT; -.
DR PDBsum; 3F62; -.
DR PDBsum; 4EEE; -.
DR PDBsum; 4EKX; -.
DR PDBsum; 4HJJ; -.
DR ProteinModelPortal; Q14116; -.
DR SMR; Q14116; 37-193.
DR DIP; DIP-3785N; -.
DR IntAct; Q14116; 1.
DR STRING; 9606.ENSP00000280357; -.
DR PhosphoSite; Q14116; -.
DR DMDM; 3219817; -.
DR OGP; Q14116; -.
DR PaxDb; Q14116; -.
DR PRIDE; Q14116; -.
DR DNASU; 3606; -.
DR Ensembl; ENST00000280357; ENSP00000280357; ENSG00000150782.
DR Ensembl; ENST00000524595; ENSP00000434561; ENSG00000150782.
DR Ensembl; ENST00000528832; ENSP00000434161; ENSG00000150782.
DR GeneID; 3606; -.
DR KEGG; hsa:3606; -.
DR UCSC; uc001pna.2; human.
DR CTD; 3606; -.
DR GeneCards; GC11M112013; -.
DR HGNC; HGNC:5986; IL18.
DR HPA; CAB007772; -.
DR HPA; CAB027385; -.
DR HPA; HPA003980; -.
DR MIM; 600953; gene.
DR neXtProt; NX_Q14116; -.
DR PharmGKB; PA29802; -.
DR eggNOG; NOG77229; -.
DR HOGENOM; HOG000048723; -.
DR HOVERGEN; HBG000388; -.
DR InParanoid; Q14116; -.
DR KO; K05482; -.
DR OMA; VPGHDDK; -.
DR OrthoDB; EOG7SR4NN; -.
DR Reactome; REACT_6900; Immune System.
DR EvolutionaryTrace; Q14116; -.
DR GeneWiki; Interleukin_18; -.
DR GenomeRNAi; 3606; -.
DR NextBio; 14093; -.
DR PMAP-CutDB; Q14116; -.
DR PRO; PR:Q14116; -.
DR ArrayExpress; Q14116; -.
DR Bgee; Q14116; -.
DR CleanEx; HS_IL18; -.
DR Genevestigator; Q14116; -.
DR GO; GO:0016324; C:apical plasma membrane; IEA:Ensembl.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005576; C:extracellular region; TAS:UniProtKB.
DR GO; GO:0005615; C:extracellular space; IEA:UniProtKB-KW.
DR GO; GO:0005125; F:cytokine activity; TAS:UniProtKB.
DR GO; GO:0001525; P:angiogenesis; IDA:UniProtKB.
DR GO; GO:0007267; P:cell-cell signaling; TAS:ProtInc.
DR GO; GO:0071320; P:cellular response to cAMP; IEA:Ensembl.
DR GO; GO:0070301; P:cellular response to hydrogen peroxide; IEA:Ensembl.
DR GO; GO:0071346; P:cellular response to interferon-gamma; IEA:Ensembl.
DR GO; GO:0071260; P:cellular response to mechanical stimulus; IEA:Ensembl.
DR GO; GO:0071407; P:cellular response to organic cyclic compound; IDA:UniProtKB.
DR GO; GO:0071374; P:cellular response to parathyroid hormone stimulus; IEA:Ensembl.
DR GO; GO:0071375; P:cellular response to peptide hormone stimulus; IEA:Ensembl.
DR GO; GO:0071356; P:cellular response to tumor necrosis factor; IEA:Ensembl.
DR GO; GO:0042033; P:chemokine biosynthetic process; TAS:UniProtKB.
DR GO; GO:0050966; P:detection of mechanical stimulus involved in sensory perception of pain; IEA:Ensembl.
DR GO; GO:0048546; P:digestive tract morphogenesis; IEA:Ensembl.
DR GO; GO:0042253; P:granulocyte macrophage colony-stimulating factor biosynthetic process; TAS:UniProtKB.
DR GO; GO:0006954; P:inflammatory response; IDA:UniProtKB.
DR GO; GO:0042095; P:interferon-gamma biosynthetic process; TAS:UniProtKB.
DR GO; GO:0042231; P:interleukin-13 biosynthetic process; TAS:UniProtKB.
DR GO; GO:0042094; P:interleukin-2 biosynthetic process; TAS:UniProtKB.
DR GO; GO:0031663; P:lipopolysaccharide-mediated signaling pathway; IDA:UniProtKB.
DR GO; GO:0030324; P:lung development; IEA:Ensembl.
DR GO; GO:0000165; P:MAPK cascade; IMP:UniProtKB.
DR GO; GO:0030101; P:natural killer cell activation; IEA:Ensembl.
DR GO; GO:0001649; P:osteoblast differentiation; IEA:Ensembl.
DR GO; GO:0042104; P:positive regulation of activated T cell proliferation; IDA:UniProtKB.
DR GO; GO:2000504; P:positive regulation of blood vessel remodeling; IEA:Ensembl.
DR GO; GO:0032722; P:positive regulation of chemokine production; IEA:Ensembl.
DR GO; GO:0032967; P:positive regulation of collagen biosynthetic process; IEA:Ensembl.
DR GO; GO:0010628; P:positive regulation of gene expression; IEA:Ensembl.
DR GO; GO:0032725; P:positive regulation of granulocyte macrophage colony-stimulating factor production; IDA:BHF-UCL.
DR GO; GO:0050729; P:positive regulation of inflammatory response; IC:BHF-UCL.
DR GO; GO:0032729; P:positive regulation of interferon-gamma production; IDA:BHF-UCL.
DR GO; GO:0032731; P:positive regulation of interleukin-1 beta production; IEA:Ensembl.
DR GO; GO:0032740; P:positive regulation of interleukin-17 production; IDA:BHF-UCL.
DR GO; GO:0032757; P:positive regulation of interleukin-8 production; IEA:Ensembl.
DR GO; GO:2000256; P:positive regulation of male germ cell proliferation; IEA:Ensembl.
DR GO; GO:0032819; P:positive regulation of natural killer cell proliferation; IDA:BHF-UCL.
DR GO; GO:0043525; P:positive regulation of neuron apoptotic process; IEA:Ensembl.
DR GO; GO:0042346; P:positive regulation of NF-kappaB import into nucleus; IEA:Ensembl.
DR GO; GO:0051142; P:positive regulation of NK T cell proliferation; IDA:BHF-UCL.
DR GO; GO:0032930; P:positive regulation of superoxide anion generation; IEA:Ensembl.
DR GO; GO:0034105; P:positive regulation of tissue remodeling; IC:BHF-UCL.
DR GO; GO:0032760; P:positive regulation of tumor necrosis factor production; IEA:Ensembl.
DR GO; GO:0043117; P:positive regulation of vascular permeability; IEA:Ensembl.
DR GO; GO:0030155; P:regulation of cell adhesion; IDA:UniProtKB.
DR GO; GO:0009409; P:response to cold; IEA:Ensembl.
DR GO; GO:0055093; P:response to hyperoxia; IEA:Ensembl.
DR GO; GO:0001666; P:response to hypoxia; IEA:Ensembl.
DR GO; GO:0009314; P:response to radiation; IEA:Ensembl.
DR GO; GO:0030431; P:sleep; ISS:UniProtKB.
DR GO; GO:0042088; P:T-helper 1 type immune response; IDA:UniProtKB.
DR GO; GO:0042092; P:type 2 immune response; TAS:UniProtKB.
DR InterPro; IPR008996; Cytokine_IL1-like.
DR InterPro; IPR000975; IL-1.
DR InterPro; IPR015529; IL-18.
DR PANTHER; PTHR11326; PTHR11326; 1.
DR Pfam; PF00340; IL1; 1.
DR PIRSF; PIRSF015162; Interleukin_18; 1.
DR PRINTS; PR01933; INTRLEUKIN18.
DR SMART; SM00125; IL1; 1.
DR SUPFAM; SSF50353; SSF50353; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Complete proteome; Cytokine;
KW Reference proteome; Secreted.
FT PROPEP 1 36 By similarity.
FT /FTId=PRO_0000015343.
FT CHAIN 37 193 Interleukin-18.
FT /FTId=PRO_0000015344.
FT VAR_SEQ 27 30 Missing (in isoform 2).
FT /FTId=VSP_044934.
FT CONFLICT 66 66 F -> L (in Ref. 3; AAC27787).
FT CONFLICT 86 86 S -> R (in Ref. 3; AAC27787).
FT CONFLICT 191 191 N -> S (in Ref. 3; AAC27787).
FT STRAND 42 49
FT STRAND 55 58
FT STRAND 64 67
FT HELIX 71 76
FT TURN 77 81
FT STRAND 83 91
FT TURN 92 94
FT STRAND 95 111
FT HELIX 113 115
FT STRAND 118 121
FT STRAND 126 131
FT STRAND 137 142
FT STRAND 145 156
FT STRAND 159 166
FT STRAND 169 176
FT TURN 178 180
FT HELIX 183 185
FT STRAND 187 191
SQ SEQUENCE 193 AA; 22326 MW; 323C62C203788D55 CRC64;
MAAEPVEDNC INFVAMKFID NTLYFIAEDD ENLESDYFGK LESKLSVIRN LNDQVLFIDQ
GNRPLFEDMT DSDCRDNAPR TIFIISMYKD SQPRGMAVTI SVKCEKISTL SCENKIISFK
EMNPPDNIKD TKSDIIFFQR SVPGHDNKMQ FESSSYEGYF LACEKERDLF KLILKKEDEL
GDRSIMFTVQ NED
//
MIM
600953
*RECORD*
*FIELD* NO
600953
*FIELD* TI
*600953 INTERLEUKIN 18; IL18
;;INTERFERON-GAMMA-INDUCING FACTOR; IGIF
*FIELD* TX
CLONING
read more
Okamura et al. (1995) cloned an interferon-gamma (IFNG; 147570)-inducing
factor that augments natural killer (NK) cell activity in spleen cells.
The gene encodes a precursor protein of 192 amino acids and a mature
protein of 157 amino acids. Messenger RNAs for the gene, designated IGIF
by them, and for interleukin-12 (IL12; see 161560) were readily detected
in Kupffer cells and activated macrophages. Recombinant IGIF induced
IFNG more potently than did IL12, which is also a NK-cell stimulatory
factor. Administration of anti-IGIF antibodies prevented liver damage in
mice inoculated with Propionibacterium acnes and challenged with
lipopolysaccharide that induces toxic shock. Okamura et al. (1995)
speculated that IGIF may be involved in the development of Th1 cells and
also in mechanisms of tissue injury in inflammatory reactions. The
interferon-gamma-inducing factor is also known as interleukin-18
(Sarvetnick, 1997).
GENE STRUCTURE
Sanchez et al. (2009) noted that the IL18 gene contains 6 exons.
MAPPING
By analysis of a human/rodent somatic cell hybrid panel and radiation
hybrid analysis, Nolan et al. (1998) mapped the IL18 gene to
11q22.2-q22.3, close to the DRD2 (126450) gene.
GENE FUNCTION
The adhesion of circulating cancer cells to capillary endothelia is a
critical step in the initiation of metastasis. Vidal-Vanaclocha et al.
(2000) reported results demonstrating a role for interleukin-1-beta
(IL1B; 147720) and IL18 in the development of hepatic metastases of
melanoma in vivo. In vitro, soluble products from mouse melanoma cells
stimulated hepatic sinusoidal endothelium to sequentially release tumor
necrosis factor-alpha (TNFA; 191160), IL1B, and IL18. The IL18 cytokine
increased expression of vascular cell adhesion molecule-1 (VCAM1;
192225) and the adherence of melanoma cells.
Shida et al. (2001) found that 30% of normal subjects had a detectable,
functionally inactive IL18 fragment, which they termed IL18 type 2,
bound to IgM in plasma. The level of IL18 type 2 was 10- to 100-fold
higher than that of conventional, active IL18 type 1 in these subjects.
Using RT-PCR, immunoblot, and immunofluorescence microscopy analyses,
Sugawara et al. (2001) demonstrated that oral epithelial cells express
IL18 mRNA and the 24-kD IL18 precursor protein. ELISA analysis showed
that stimulation of the cells with proteinase-3 (PRTN3; 177020) and
lipopolysaccharide (LPS) after IFNG priming leads to intracellular
production and secretion of the 18-kD bioactive form of IL18 in a
caspase-1 (CASP1; 147678)-independent fashion. Cell fractionation and
immunoblot analyses indicated that PRTN3 acts on the cell surface after
the IFNG priming, not intracellularly. Sugawara et al. (2001) proposed
that PRTN3 together with LPS and IFNG may be involved in mucosal
inflammation, such as periodontitis.
Pizarro et al. (1999) detected increased IL18 mRNA and protein
expression in intestinal epithelial cells and lamina propria mononuclear
cells in Crohn disease tissue compared with ulcerative colitis (see
266600) and normal tissue.
By immunohistochemical analysis, Corbaz et al. (2002) showed that
IL18-binding protein (IL18BP; 604113) expression in intestinal tissue is
increased in endothelial cells as well as cells of the submucosa and
overlying lymphoid aggregates in Crohn disease patients compared with
controls. Immunofluorescent microscopy demonstrated colocalization with
macrophage and endothelial cell markers, but not with those of
lymphocytes or epithelial cells. Real-time PCR and ELISA analysis
detected increased levels of both IL18 and IL18BP in the Crohn disease
intestinal tissue. Unbound neutralizing isoforms a and c of IL18BP were
in excess compared with IL18 in the Crohn disease patients, indicating
that IL18BP upregulation correlates with increased IL18 expression in
Crohn disease. Corbaz et al. (2002) suggested that despite the presence
of IL18BP, which has been shown to ameliorate colitis in a mouse model
(ten Hove et al., 2001), some IL18 activity may be available for
perpetuating the pathogenesis of Crohn disease.
Henao-Mejia et al. (2012) demonstrated that NLRP6 (609650) and NLRP3
(606416) inflammasomes and the effector protein IL18 negatively regulate
nonalcoholic fatty liver disease/nonalcoholic steatohepatitis
progression, as well as multiple aspects of metabolic syndrome via
modulation of the gut microbiota. Different mouse models revealed that
inflammasome deficiency-associated changes in the configuration of the
gut microbiota are associated with exacerbated hepatic steatosis and
inflammation through influx of TLR4 (603030) and TLR9 (605474) agonists
into the portal circulation, leading to enhanced hepatic TNFA
expression, which drives NASH progression. Furthermore, cohousing of
inflammasome-deficient mice with wildtype mice resulted in exacerbation
of hepatic steatosis and obesity. Thus, Henao-Mejia et al. (2012)
concluded that altered interactions between the gut microbiota and the
host, produced by defective NLRP3 and NLRP6 inflammasome sensing, may
govern the rate of progression of multiple metabolic syndrome-associated
abnormalities, highlighting the central role of the microbiota in the
pathogenesis of theretofore seemingly unrelated systemic
autoinflammatory and metabolic disorders.
- Involvement in Coronary Artery Disease
Mallat et al. (2001) examined stable and unstable human carotid
atherosclerotic plaques retrieved by endarterectomy for the presence of
IL18 and found that IL18 was highly expressed in the atherosclerotic
plaques compared to normal control arteries and was localized mainly in
plaque macrophages. Significantly higher levels of IL18 mRNA were found
in symptomatic (unstable) plaques than asymptomatic (stable) plaques.
Mallat et al. (2001) suggested that IL18 plays a major role in
atherosclerotic plaque destabilization leading to acute ischemic
syndromes.
In a prospective study of 1,229 patients with documented coronary artery
disease, Blankenberg et al. (2002) measured baseline serum
concentrations of IL18 and other markers of inflammation. Median serum
IL18 levels were significantly higher among patients who had a fatal
cardiovascular event during the follow-up period (median, 3.9 years)
than among those who did not. After adjustment for potential
confounders, the relationship remained and was observed in both patients
with stable angina and those with unstable angina at baseline.
Blankenberg et al. (2002) concluded that serum IL18 is a strong
independent predictor of death from cardiovascular causes in patients
with coronary artery disease regardless of clinical status at admission.
Blankenberg et al. (2003) evaluated the relationship between baseline
plasma levels of IL18 and the subsequent incidence of coronary events
over a 5-year follow-up in healthy European men aged 50 to 59 years.
Baseline levels of IL18 were significantly higher in 335 European men
who had a coronary event than in 670 age-matched controls (p = 0.005).
In all models, IL18 made an independent contribution to the prediction
of risk over lipids or other inflammatory markers.
Francisella tularensis, the causative agent of tularemia and a potential
biohazard threat, evades the immune response, including innate responses
through the lipopolysaccharide receptor TLR4 (603030), thus increasing
its virulence. Huang et al. (2010) deleted the bacterium's ripA gene and
found that mouse macrophages and a human monocyte line produced
significant amounts of the inflammatory cytokines TNF, IL18, and IL1B in
response to the mutant. IL1B and IL18 secretion was dependent on PYCARD
(606838) and CASP1, and MYD88 (602170) was required for inflammatory
cytokine synthesis. A complemented strain with restored expression of
ripA restored immune evasion, as well as activation of the MAP kinases
ERK1 (MAPK3; 601795)/ERK2 (MAPK1; 176948), JNK (see 601158), and p38
(MAPK14; 600289). Phamacologic inhibition of these MAPKs reduced
cytokine induction by the ripA deletion mutant. Mice infected with the
mutant exhibited stronger Il1b and Tnfa responses than mice infected
with the wildtype live vaccine strain. Huang et al. (2010) concluded
that the F. tularensis ripA gene product functions by suppressing MAPK
pathways and circumventing the inflammasome response.
MOLECULAR GENETICS
Tiret et al. (2005) genotyped 22 polymorphisms of the IL18, IL18R1
(604494), IL18RAP (604509), and IL18BP (604113) genes in 1,288 patients
with coronary artery disease who were followed for a median of 5.9
years. Baseline IL18 levels were predictive of cardiovascular deaths
occurring within the first 4 years but not of later deaths. Haplotypes
of the IL18 gene were associated with IL18 levels and cardiovascular
mortality after adjustment for cardiovascular risk factors; adjustment
for baseline IL18 levels abolished the association. Tiret et al. (2005)
concluded that variations of the IL18 gene influence circulating levels
of IL18 and clinical outcome in patients with coronary artery disease.
- Associations Pending Confirmation
Lee et al. (2007) reported a significantly higher frequency of the 105A
allele of the IL18 105A-C SNP in Chinese rheumatoid arthritis (RA;
180300) patients compared with controls. The relative risk of rheumatoid
arthritis was stronger in 105A homozygotes.
Sanchez et al. (2009) selected 9 SNPs spanning the IL18 gene and
genotyped an independent set of 752 Spanish systemic lupus erythematosis
(SLE; 152700) patients and 595 Spanish controls. A -1297T-C SNP (dbSNP
rs360719) survived correction for multiple tests and was genotyped in 2
case-control replication cohorts from Italy and Argentina. Combined
analysis for the risk C allele remained significant (pooled odds ratio =
1.37, 95% CI 1.21-1.54, corrected p = 1.16 x 10(-6)). There was a
significant increase in the relative expression of IL18 mRNA in
individuals carrying the risk -1297C allele; in addition, -1297C allele
created a binding site for the transcriptional factor OCT1 (POU2F1;
164175). Sanchez et al. (2009) suggested that the dbSNP rs360719 variant
may play a role in susceptibility to SLE and in IL18 expression.
ANIMAL MODEL
Rothe et al. (1997) concluded that IGIF expression is abnormally
regulated in NOD mice and is closely associated with diabetes
development. They showed that the Igif gene maps to mouse chromosome 9
within the Idd2 interval and is therefore a candidate for the Idd2
diabetes susceptibility gene.
Okamoto et al. (2000) showed that Il18 has a protective effect against
the development of chronic graft-versus-host disease (GVHD; see 614395)
in mouse. Using a murine bone marrow transplant (BMT) model, Reddy et
al. (2001) showed that blockade of Il18 accelerated acute GVHD
mortality. In contrast, Il18 administration reduced serum Tnf and
lipopolysaccharide levels, decreased intestinal pathology, attenuated
early donor T-cell expansion, increased Fas (TNFRSF6; 134637) expression
and apoptosis in donor T cells, and enhanced survival. With
Fas-deficient or Ifng knockout donor mice, Il18 did not protect BMT
recipients from acute GVHD. Reddy et al. (2001) concluded that IL18
regulates acute GVHD by enhancing FAS-mediated apoptosis of donor T
cells early after BMT in an IFNG-dependent manner.
In transgenic mice, Konishi et al. (2002) showed that IL18 contributes
to the spontaneous development of atopic dermatitis-like inflammatory
skin lesions independently of IgE/Stat6 (601512) under specific
pathogen-free conditions. Overrelease of IL18 initiated atopic
dermatitis-like inflammation, which was accelerated by interleukin
1-alpha (IL1A; 147760).
The lupus-like autoimmune syndrome of mice (lpr) is characterized by
progressive lymphadenopathy and autoantibody production, leading to
early death from renal failure. Activation of T helper lymphocytes is
one of the events in the pathogenesis of the disease in these mice and
likely in human systemic lupus erythematosus (SLE; 152700). Among T
helper lymphocyte-dependent cytokines, interferon-gamma plays a pivotal
role in the abnormal cell activation and the fatal development of the
lpr disease. IL18, an inducer of IFN-gamma in T lymphocytes and NK
cells, may contribute to the disease because cells from lpr mice are
hypersensitive to Il18 and express high levels of Il18. To assess the
contribution of Il18 to the pathogenesis in the animal model, Bossu et
al. (2003) attempted in vivo inhibition of Il18. Young lpr mice were
vaccinated against autologous Il18 by repeated administration of a cDNA
coding for the murine Il18 precursor. Vaccinated mice produced
autoantibodies to murine Il18 and exhibited a significant reduction in
spontaneous lymphoproliferation and IFN-gamma production as well as less
glomerulonephritis and renal damage. Moreover, mortality was
significantly delayed in anti-Il18-vaccinated mice. Bossu et al. (2003)
concluded that Il18 plays a major role in the pathogenesis of the
autoimmune syndrome of lpr mice and that a reduction in IL18 activity
could be a therapeutic strategy in autoimmune diseases.
Van Der Sluijs et al. (2005) found that Il18 -/- mice recovered from
influenza virus infection with a lower viral load in lungs and a greater
gain in body weight compared with wildtype mice. No differences could be
detected in Ifng levels, but Il18 -/- mice had significantly reduced Tnf
and Mcp1 (CCL2; 158105). There were no differences in mortality between
wildtype and Il18 -/- mice following challenge with a lethal dose of
influenza. Van Der Sluijs et al. (2005) concluded that IL18 is
upregulated in lung after influenza infection and that IL18 deficiency
is associated with accelerated viral clearance and enhanced activation
of CD4 (186940)-positive T cells.
Netea et al. (2006) noted that, in contrast to other proinflammatory
cytokines, there is a constitutive intracellular pool of pro-IL18. After
cleavage of pro-IL18 by CASP1, IL18 bioactivity is kept in balance by
high concentrations of IL18BP in blood and tissues. IL18 concentrations
are increased in individuals with type 2 IDDM (125852), obesity, or
polycystic ovary syndrome (see 184700). Netea et al. (2006) found that
mice deficient in Il18 had markedly increased body weight compared with
wildtype littermates after 3 months of age and displayed obesity,
insulin resistance, hyperglycemia, lipid abnormalities, and
atherosclerosis. The weight gain was associated with significantly
increased body fat, food intake, glucose, insulin, glucagon,
cholesterol, and leptin (LEP; 164160). Histologic analysis of various
organs showed only increased size of pancreatic islets in mutant mice.
Leptin administration or intracerebral, but not intravenous,
administration of recombinant Il18 reduced food intake. Intraperitoneal
administration of recombinant Il18 restored insulin sensitivity and
corrected hyperglycemia through activation of Stat3 (102582)
phosphorylation in Il18 -/- mice. Il18r -/- and Il18bp transgenic mice
had phenotypes similar to that of Il18 -/- mice. Netea et al. (2006)
concluded that IL18 has an important role in homeostasis of energy
intake and insulin sensitivity.
*FIELD* RF
1. Blankenberg, S.; Luc, G.; Ducimetiere, P.; Arveiler, D.; Ferrieres,
J.; Amouyel, P.; Evans, A.; Cambien, F.; Tiret, L.: Interleukin-18
and the risk of coronary heart disease in European men: the prospective
epidemiological study of myocardial infarction (PRIME). Circulation 108:
2453-2459, 2003.
2. Blankenberg, S.; Tiret, L.; Bickel, C.; Peetz, D.; Cambien, F.;
Meyer, J.; Rupprecht, H. J.: Interleukin-18 is a strong predictor
of cardiovascular death in stable and unstable angina. Circulation 106:
24-30, 2002.
3. Bossu, P.; Neumann, D.; Del Giudice, E.; Ciaramella, A.; Gloaguen,
I.; Fantuzzi, G.; Dinarello, C. A.; Di Carlo, E.; Musiani, P.; Meroni,
P. L.; Caselli, G.; Ruggiero, P.; Boraschi, D.: IL-18 cDNA vaccination
protects mice from spontaneous lupus-like autoimmune disease. Proc.
Nat. Acad. Sci. 100: 14181-14186, 2003.
4. Corbaz, A.; ten Hove, T.; Herren, S.; Graber, P.; Schwartsburd,
B.; Belzer, I.; Harrison, J.; Plitz, T.; Kosco-Vilbois, M. H.; Kim,
S.-H.; Dinarello, C. A.; Novick, D.; van Deventer, S.; Chvatchko,
Y.: IL-18-binding protein expression by endothelial cells and macrophages
is up-regulated during active Crohn's disease. J. Immun. 168: 3608-3616,
2002.
5. Henao-Mejia, J.; Elinav, E.; Jin, C.; Hao, L.; Mehal, W. Z.; Strowig,
T.; Thaiss, C. A.; Kau, A. L.; Eisenbarth, S. C.; Jurczak, M. J.;
Camporez, J.-P.; Shulman, G. I.; Gordon, J. I.; Hoffman, H. M.; Flavell,
R. A.: Inflammasome-mediated dysbiosis regulates progression of NAFLD
and obesity. Nature 482: 179-185, 2012.
6. Huang, M. T.-H.; Mortensen, B. L.; Taxman, D. J.; Craven, R. R.;
Taft-Benz, S.; Kijek, T. M.; Fuller, J. R.; Davis, B. K.; Allen, I.
C.; Brickey, W. J.; Gris, D.; Wen, H.; Kawula, T. H.; Ting, J. P.-Y.
: Deletion of ripA alleviates suppression of the inflammasome and
MAPK by Francisella tularensis. J. Immun. 185: 5476-5485, 2010.
7. Konishi, H.; Tsutsui, H.; Murakami, T.; Yumikura-Futatsugi, S.;
Yamanaka, K.; Tanaka, M.; Iwakura, Y.; Suzuki, N.; Takeda, K.; Akira,
S.; Nakanishi, K.; Mizutani, H.: IL-18 contributes to the spontaneous
development of atopic dermatitis-like inflammatory skin lesion independently
of IgE/stat6 under specific pathogen-free conditions. Proc. Nat.
Acad. Sci. 99: 11340-11345, 2002.
8. Lee, C.-C.; Lin, W.-Y.; Wan, L.; Tsai, Y.; Lin, Y.-J.; Tsai, C.-H.;
Huang, C.-M.; Tsai, F.-J.: Interleukin-18 gene polymorphism, but
not interleukin-2 gene polymorphism, is associated with rheumatoid
arthritis. Immunogenetics 59: 433-439, 2007.
9. Mallat, Z.; Corbaz, A.; Scoazec, A.; Besnard, S.; Leseche, G.;
Chvatchko, Y.; Tedgui, A.: Expression of interleukin-18 in human
atherosclerotic plaques and relation to plaque instability. Circulation 104:
1598-1603, 2001.
10. Netea, M. G.; Joosten, L. A. B.; Lewis, E.; Jensen, D. R.; Voshol,
P. J.; Kullberg, B. J.; Tack, C. J.; van Krieken, H.; Kim, S.-H.;
Stalenhoef, A. F.; van de Loo, F. A.; Verschueren, I.; Pulawa, L.;
Akira, S.; Eckel, R. H.; Dinarello, C. A.; van den Berg, W.; van der
Meer, J. W. M.: Deficiency of interleukin-18 in mice leads to hyperphagia,
obesity and insulin resistance. Nature Med. 12: 650-656, 2006.
11. Nolan, K. F.; Greaves, D. R.; Waldmann, H.: The human interleukin
18 gene IL18 maps to 11q22.2-q22.3, closely linked to the DRD2 gene
locus and distinct from mapped IDDM loci. Genomics 51: 161-163,
1998.
12. Okamoto, I.; Kohno, K.; Tanimoto, T.; Iwaki, K.; Ishihara, T.;
Akamatsu, S.; Ikegami, H.; Kurimoto, M.: IL-18 prevents the development
of chronic graft-versus-host disease in mice. J. Immun. 164: 6067-6074,
2000.
13. Okamura, H.; Tsutsui, H.; Komatsu, T.; Yutsudo, M.; Hakura, A.;
Tanimoto, T.; Torigoe, K.; Okura, T.; Nukada, Y.; Hattori, K.; Akita,
K.; Namba, M.; Tanabe, F.; Konishi, K.; Fukuda, S.; Kurimoto, M.:
Cloning of a new cytokine that induces IFN-gamma production by T cells. Nature 378:
88-91, 1995.
14. Pizarro, T. T.; Michie, M. H.; Bentz, M.; Woraratanadharm, J.;
Smith, M. F., Jr.; Foley, E.; Moskaluk, C. A.; Bickston, S. J.; Cominelli,
F.: IL-18, a novel immunoregulatory cytokine, is up-regulated in
Crohn's disease: expression and localization in intestinal mucosal
cells. J. Immun. 162: 6829-6835, 1999.
15. Reddy, P.; Teshima, T.; Kukuruga, M.; Ordemann, R.; Liu, C.; Lowler,
K.; Ferrara, J. L. M.: Interleukin-18 regulates acute graft-versus-host
disease by enhancing Fas-mediated donor T cell apoptosis. J. Exp.
Med. 194: 1433-1440, 2001.
16. Rothe, H.; Jenkins, N. A.; Copeland, N. G.; Kolb, H.: Active
stage of autoimmune diabetes is associated with the expression of
a novel cytokine, IGIF, which is located near Idd2. J. Clin. Invest. 99:
469-474, 1997.
17. Sanchez, E.; Palomino-Morales, R. J.; Ortego-Centeno, N.; Jimenez-Alonso,
J.; Gonzalez-Gay, M. A.; Lopez-Nevot, M. A.; Sanchez-Roman, J.; de
Ramon, E.; Gonzalez-Escribano, M. F.; Pons-Estel, B. A.; D'Alfonso,
S.; Sebastiani, G. D.; Italian Collaborative Group; Alarcon-Riquelme,
M. E.; Martin, J.: Identification of a new putative functional IL18
gene variant through an association study in systemic lupus erythematosus. Hum.
Molec. Genet. 18: 3739-3748, 2009.
18. Sarvetnick, N.: IFN-gamma, IGIF, and IDDM. (Editorial) J. Clin.
Invest. 99: 371-372, 1997.
19. Shida, K.; Shiratori, I.; Matsumoto, M.; Fukumori, Y.; Matsuhisa,
A.; Kikkawa, S.; Tsuji, S.; Okamura, H.; Toyoshima, K.; Seya, T.:
An alternative form of IL-18 in human blood plasma: complex formation
with IgM defined by monoclonal antibodies. J. Immun. 166: 6671-6679,
2001.
20. Sugawara, S.; Uehara, A.; Nochi, T.; Yamaguchi, T.; Ueda, H.;
Sugiyama, A.; Hanzawa, K.; Kumagai, K.; Okamura, H.; Takada, H.:
Neutrophil proteinase 3-mediated induction of bioactive IL-18 secretion
by human oral epithelial cells. J. Immun. 167: 6568-6575, 2001.
21. ten Hove, T.; Corbaz, A.; Amitai, H.; Aloni, S.; Belzer, I.; Graber,
P.; Drillenburg, P.; van Deventer, S. J. H.; Chvatchko, Y.; te Velde,
A. A.: Blockade of endogenous IL-18 ameliorates TNBS-induced colitis
by decreasing local TNF-alpha production in mice. Gastroenterology 121:
1372-1379, 2001.
22. Tiret, L.; Godefroy, T.; Lubos, E.; Nicaud, V.; Tregouet, D.-A.;
Barbaux, S.; Schnabel, R.; Bickel, C.; Espinola-Klein, C.; Poirier,
O.; Perret, C.; Munzel, T.; Rupprecht, H.-J.; Lackner, K.; Cambien,
F.; Blankenberg, S.: Genetic analysis of the interleukin-18 system
highlights the role of the interleukin-18 gene in cardiovascular disease. Circulation 112:
643-650, 2005.
23. Van Der Sluijs, K. F.; Van Elden, L. J. R.; Arens, R.; Nijhuis,
M.; Schuurman, R.; Florquin, S.; Kwakkel, J.; Akira, S.; Jansen, H.
M.; Lutter, R.; Van Der Polls, T.: Enhanced viral clearance in interleukin-18
gene-deficient mice after pulmonary infection with influenza A virus. Immunology 114:
112-120, 2005.
24. Vidal-Vanaclocha, F.; Fantuzzi, G.; Mendoza, L.; Fuentes, A. M.;
Anasagasti, M. J.; Martin, J.; Carrascal, T.; Walsh, P.; Reznikov,
L. L.; Kim, S.-H.; Novick, D.; Rubinstein, M.; Dinarello, C. A.:
IL-18 regulates IL-1-beta-dependent hepatic melanoma metastasis via
vascular cell adhesion molecule-1. Proc. Nat. Acad. Sci. 97: 734-739,
2000.
*FIELD* CN
Ada Hamosh - updated: 3/7/2012
Paul J. Converse - updated: 2/9/2011
George E. Tiller - updated: 7/8/2010
Paul J. Converse - updated: 6/26/2008
Paul J. Converse - updated: 7/20/2006
Paul J. Converse - updated: 4/11/2006
Marla J. F. O'Neill - updated: 4/6/2006
Marla J. F. O'Neill - updated: 2/15/2006
Victor A. McKusick - updated: 12/3/2004
Victor A. McKusick - updated: 10/9/2002
Paul J. Converse - updated: 5/8/2002
Paul J. Converse - updated: 2/20/2002
Paul J. Converse - updated: 1/17/2002
Paul J. Converse - updated: 10/17/2001
Victor A. McKusick - updated: 2/9/2000
Carol A. Bocchini - updated: 4/4/1999
Victor A. McKusick - updated: 3/16/1997
*FIELD* CD
Victor A. McKusick: 12/8/1995
*FIELD* ED
alopez: 03/09/2012
terry: 3/7/2012
mgross: 12/16/2011
mgross: 2/9/2011
wwang: 7/23/2010
terry: 7/8/2010
carol: 8/14/2008
mgross: 7/8/2008
terry: 6/26/2008
mgross: 8/4/2006
terry: 7/20/2006
mgross: 5/2/2006
terry: 4/11/2006
wwang: 4/7/2006
terry: 4/6/2006
carol: 2/15/2006
tkritzer: 12/8/2004
terry: 12/3/2004
tkritzer: 7/15/2003
tkritzer: 10/9/2002
mgross: 5/8/2002
mgross: 2/20/2002
mgross: 1/17/2002
mgross: 10/17/2001
mgross: 3/1/2000
terry: 2/9/2000
mgross: 4/6/1999
carol: 4/4/1999
psherman: 1/5/1999
alopez: 6/19/1998
mark: 7/30/1997
alopez: 7/24/1997
mark: 3/16/1997
terry: 3/10/1997
mark: 12/8/1995
*RECORD*
*FIELD* NO
600953
*FIELD* TI
*600953 INTERLEUKIN 18; IL18
;;INTERFERON-GAMMA-INDUCING FACTOR; IGIF
*FIELD* TX
CLONING
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Okamura et al. (1995) cloned an interferon-gamma (IFNG; 147570)-inducing
factor that augments natural killer (NK) cell activity in spleen cells.
The gene encodes a precursor protein of 192 amino acids and a mature
protein of 157 amino acids. Messenger RNAs for the gene, designated IGIF
by them, and for interleukin-12 (IL12; see 161560) were readily detected
in Kupffer cells and activated macrophages. Recombinant IGIF induced
IFNG more potently than did IL12, which is also a NK-cell stimulatory
factor. Administration of anti-IGIF antibodies prevented liver damage in
mice inoculated with Propionibacterium acnes and challenged with
lipopolysaccharide that induces toxic shock. Okamura et al. (1995)
speculated that IGIF may be involved in the development of Th1 cells and
also in mechanisms of tissue injury in inflammatory reactions. The
interferon-gamma-inducing factor is also known as interleukin-18
(Sarvetnick, 1997).
GENE STRUCTURE
Sanchez et al. (2009) noted that the IL18 gene contains 6 exons.
MAPPING
By analysis of a human/rodent somatic cell hybrid panel and radiation
hybrid analysis, Nolan et al. (1998) mapped the IL18 gene to
11q22.2-q22.3, close to the DRD2 (126450) gene.
GENE FUNCTION
The adhesion of circulating cancer cells to capillary endothelia is a
critical step in the initiation of metastasis. Vidal-Vanaclocha et al.
(2000) reported results demonstrating a role for interleukin-1-beta
(IL1B; 147720) and IL18 in the development of hepatic metastases of
melanoma in vivo. In vitro, soluble products from mouse melanoma cells
stimulated hepatic sinusoidal endothelium to sequentially release tumor
necrosis factor-alpha (TNFA; 191160), IL1B, and IL18. The IL18 cytokine
increased expression of vascular cell adhesion molecule-1 (VCAM1;
192225) and the adherence of melanoma cells.
Shida et al. (2001) found that 30% of normal subjects had a detectable,
functionally inactive IL18 fragment, which they termed IL18 type 2,
bound to IgM in plasma. The level of IL18 type 2 was 10- to 100-fold
higher than that of conventional, active IL18 type 1 in these subjects.
Using RT-PCR, immunoblot, and immunofluorescence microscopy analyses,
Sugawara et al. (2001) demonstrated that oral epithelial cells express
IL18 mRNA and the 24-kD IL18 precursor protein. ELISA analysis showed
that stimulation of the cells with proteinase-3 (PRTN3; 177020) and
lipopolysaccharide (LPS) after IFNG priming leads to intracellular
production and secretion of the 18-kD bioactive form of IL18 in a
caspase-1 (CASP1; 147678)-independent fashion. Cell fractionation and
immunoblot analyses indicated that PRTN3 acts on the cell surface after
the IFNG priming, not intracellularly. Sugawara et al. (2001) proposed
that PRTN3 together with LPS and IFNG may be involved in mucosal
inflammation, such as periodontitis.
Pizarro et al. (1999) detected increased IL18 mRNA and protein
expression in intestinal epithelial cells and lamina propria mononuclear
cells in Crohn disease tissue compared with ulcerative colitis (see
266600) and normal tissue.
By immunohistochemical analysis, Corbaz et al. (2002) showed that
IL18-binding protein (IL18BP; 604113) expression in intestinal tissue is
increased in endothelial cells as well as cells of the submucosa and
overlying lymphoid aggregates in Crohn disease patients compared with
controls. Immunofluorescent microscopy demonstrated colocalization with
macrophage and endothelial cell markers, but not with those of
lymphocytes or epithelial cells. Real-time PCR and ELISA analysis
detected increased levels of both IL18 and IL18BP in the Crohn disease
intestinal tissue. Unbound neutralizing isoforms a and c of IL18BP were
in excess compared with IL18 in the Crohn disease patients, indicating
that IL18BP upregulation correlates with increased IL18 expression in
Crohn disease. Corbaz et al. (2002) suggested that despite the presence
of IL18BP, which has been shown to ameliorate colitis in a mouse model
(ten Hove et al., 2001), some IL18 activity may be available for
perpetuating the pathogenesis of Crohn disease.
Henao-Mejia et al. (2012) demonstrated that NLRP6 (609650) and NLRP3
(606416) inflammasomes and the effector protein IL18 negatively regulate
nonalcoholic fatty liver disease/nonalcoholic steatohepatitis
progression, as well as multiple aspects of metabolic syndrome via
modulation of the gut microbiota. Different mouse models revealed that
inflammasome deficiency-associated changes in the configuration of the
gut microbiota are associated with exacerbated hepatic steatosis and
inflammation through influx of TLR4 (603030) and TLR9 (605474) agonists
into the portal circulation, leading to enhanced hepatic TNFA
expression, which drives NASH progression. Furthermore, cohousing of
inflammasome-deficient mice with wildtype mice resulted in exacerbation
of hepatic steatosis and obesity. Thus, Henao-Mejia et al. (2012)
concluded that altered interactions between the gut microbiota and the
host, produced by defective NLRP3 and NLRP6 inflammasome sensing, may
govern the rate of progression of multiple metabolic syndrome-associated
abnormalities, highlighting the central role of the microbiota in the
pathogenesis of theretofore seemingly unrelated systemic
autoinflammatory and metabolic disorders.
- Involvement in Coronary Artery Disease
Mallat et al. (2001) examined stable and unstable human carotid
atherosclerotic plaques retrieved by endarterectomy for the presence of
IL18 and found that IL18 was highly expressed in the atherosclerotic
plaques compared to normal control arteries and was localized mainly in
plaque macrophages. Significantly higher levels of IL18 mRNA were found
in symptomatic (unstable) plaques than asymptomatic (stable) plaques.
Mallat et al. (2001) suggested that IL18 plays a major role in
atherosclerotic plaque destabilization leading to acute ischemic
syndromes.
In a prospective study of 1,229 patients with documented coronary artery
disease, Blankenberg et al. (2002) measured baseline serum
concentrations of IL18 and other markers of inflammation. Median serum
IL18 levels were significantly higher among patients who had a fatal
cardiovascular event during the follow-up period (median, 3.9 years)
than among those who did not. After adjustment for potential
confounders, the relationship remained and was observed in both patients
with stable angina and those with unstable angina at baseline.
Blankenberg et al. (2002) concluded that serum IL18 is a strong
independent predictor of death from cardiovascular causes in patients
with coronary artery disease regardless of clinical status at admission.
Blankenberg et al. (2003) evaluated the relationship between baseline
plasma levels of IL18 and the subsequent incidence of coronary events
over a 5-year follow-up in healthy European men aged 50 to 59 years.
Baseline levels of IL18 were significantly higher in 335 European men
who had a coronary event than in 670 age-matched controls (p = 0.005).
In all models, IL18 made an independent contribution to the prediction
of risk over lipids or other inflammatory markers.
Francisella tularensis, the causative agent of tularemia and a potential
biohazard threat, evades the immune response, including innate responses
through the lipopolysaccharide receptor TLR4 (603030), thus increasing
its virulence. Huang et al. (2010) deleted the bacterium's ripA gene and
found that mouse macrophages and a human monocyte line produced
significant amounts of the inflammatory cytokines TNF, IL18, and IL1B in
response to the mutant. IL1B and IL18 secretion was dependent on PYCARD
(606838) and CASP1, and MYD88 (602170) was required for inflammatory
cytokine synthesis. A complemented strain with restored expression of
ripA restored immune evasion, as well as activation of the MAP kinases
ERK1 (MAPK3; 601795)/ERK2 (MAPK1; 176948), JNK (see 601158), and p38
(MAPK14; 600289). Phamacologic inhibition of these MAPKs reduced
cytokine induction by the ripA deletion mutant. Mice infected with the
mutant exhibited stronger Il1b and Tnfa responses than mice infected
with the wildtype live vaccine strain. Huang et al. (2010) concluded
that the F. tularensis ripA gene product functions by suppressing MAPK
pathways and circumventing the inflammasome response.
MOLECULAR GENETICS
Tiret et al. (2005) genotyped 22 polymorphisms of the IL18, IL18R1
(604494), IL18RAP (604509), and IL18BP (604113) genes in 1,288 patients
with coronary artery disease who were followed for a median of 5.9
years. Baseline IL18 levels were predictive of cardiovascular deaths
occurring within the first 4 years but not of later deaths. Haplotypes
of the IL18 gene were associated with IL18 levels and cardiovascular
mortality after adjustment for cardiovascular risk factors; adjustment
for baseline IL18 levels abolished the association. Tiret et al. (2005)
concluded that variations of the IL18 gene influence circulating levels
of IL18 and clinical outcome in patients with coronary artery disease.
- Associations Pending Confirmation
Lee et al. (2007) reported a significantly higher frequency of the 105A
allele of the IL18 105A-C SNP in Chinese rheumatoid arthritis (RA;
180300) patients compared with controls. The relative risk of rheumatoid
arthritis was stronger in 105A homozygotes.
Sanchez et al. (2009) selected 9 SNPs spanning the IL18 gene and
genotyped an independent set of 752 Spanish systemic lupus erythematosis
(SLE; 152700) patients and 595 Spanish controls. A -1297T-C SNP (dbSNP
rs360719) survived correction for multiple tests and was genotyped in 2
case-control replication cohorts from Italy and Argentina. Combined
analysis for the risk C allele remained significant (pooled odds ratio =
1.37, 95% CI 1.21-1.54, corrected p = 1.16 x 10(-6)). There was a
significant increase in the relative expression of IL18 mRNA in
individuals carrying the risk -1297C allele; in addition, -1297C allele
created a binding site for the transcriptional factor OCT1 (POU2F1;
164175). Sanchez et al. (2009) suggested that the dbSNP rs360719 variant
may play a role in susceptibility to SLE and in IL18 expression.
ANIMAL MODEL
Rothe et al. (1997) concluded that IGIF expression is abnormally
regulated in NOD mice and is closely associated with diabetes
development. They showed that the Igif gene maps to mouse chromosome 9
within the Idd2 interval and is therefore a candidate for the Idd2
diabetes susceptibility gene.
Okamoto et al. (2000) showed that Il18 has a protective effect against
the development of chronic graft-versus-host disease (GVHD; see 614395)
in mouse. Using a murine bone marrow transplant (BMT) model, Reddy et
al. (2001) showed that blockade of Il18 accelerated acute GVHD
mortality. In contrast, Il18 administration reduced serum Tnf and
lipopolysaccharide levels, decreased intestinal pathology, attenuated
early donor T-cell expansion, increased Fas (TNFRSF6; 134637) expression
and apoptosis in donor T cells, and enhanced survival. With
Fas-deficient or Ifng knockout donor mice, Il18 did not protect BMT
recipients from acute GVHD. Reddy et al. (2001) concluded that IL18
regulates acute GVHD by enhancing FAS-mediated apoptosis of donor T
cells early after BMT in an IFNG-dependent manner.
In transgenic mice, Konishi et al. (2002) showed that IL18 contributes
to the spontaneous development of atopic dermatitis-like inflammatory
skin lesions independently of IgE/Stat6 (601512) under specific
pathogen-free conditions. Overrelease of IL18 initiated atopic
dermatitis-like inflammation, which was accelerated by interleukin
1-alpha (IL1A; 147760).
The lupus-like autoimmune syndrome of mice (lpr) is characterized by
progressive lymphadenopathy and autoantibody production, leading to
early death from renal failure. Activation of T helper lymphocytes is
one of the events in the pathogenesis of the disease in these mice and
likely in human systemic lupus erythematosus (SLE; 152700). Among T
helper lymphocyte-dependent cytokines, interferon-gamma plays a pivotal
role in the abnormal cell activation and the fatal development of the
lpr disease. IL18, an inducer of IFN-gamma in T lymphocytes and NK
cells, may contribute to the disease because cells from lpr mice are
hypersensitive to Il18 and express high levels of Il18. To assess the
contribution of Il18 to the pathogenesis in the animal model, Bossu et
al. (2003) attempted in vivo inhibition of Il18. Young lpr mice were
vaccinated against autologous Il18 by repeated administration of a cDNA
coding for the murine Il18 precursor. Vaccinated mice produced
autoantibodies to murine Il18 and exhibited a significant reduction in
spontaneous lymphoproliferation and IFN-gamma production as well as less
glomerulonephritis and renal damage. Moreover, mortality was
significantly delayed in anti-Il18-vaccinated mice. Bossu et al. (2003)
concluded that Il18 plays a major role in the pathogenesis of the
autoimmune syndrome of lpr mice and that a reduction in IL18 activity
could be a therapeutic strategy in autoimmune diseases.
Van Der Sluijs et al. (2005) found that Il18 -/- mice recovered from
influenza virus infection with a lower viral load in lungs and a greater
gain in body weight compared with wildtype mice. No differences could be
detected in Ifng levels, but Il18 -/- mice had significantly reduced Tnf
and Mcp1 (CCL2; 158105). There were no differences in mortality between
wildtype and Il18 -/- mice following challenge with a lethal dose of
influenza. Van Der Sluijs et al. (2005) concluded that IL18 is
upregulated in lung after influenza infection and that IL18 deficiency
is associated with accelerated viral clearance and enhanced activation
of CD4 (186940)-positive T cells.
Netea et al. (2006) noted that, in contrast to other proinflammatory
cytokines, there is a constitutive intracellular pool of pro-IL18. After
cleavage of pro-IL18 by CASP1, IL18 bioactivity is kept in balance by
high concentrations of IL18BP in blood and tissues. IL18 concentrations
are increased in individuals with type 2 IDDM (125852), obesity, or
polycystic ovary syndrome (see 184700). Netea et al. (2006) found that
mice deficient in Il18 had markedly increased body weight compared with
wildtype littermates after 3 months of age and displayed obesity,
insulin resistance, hyperglycemia, lipid abnormalities, and
atherosclerosis. The weight gain was associated with significantly
increased body fat, food intake, glucose, insulin, glucagon,
cholesterol, and leptin (LEP; 164160). Histologic analysis of various
organs showed only increased size of pancreatic islets in mutant mice.
Leptin administration or intracerebral, but not intravenous,
administration of recombinant Il18 reduced food intake. Intraperitoneal
administration of recombinant Il18 restored insulin sensitivity and
corrected hyperglycemia through activation of Stat3 (102582)
phosphorylation in Il18 -/- mice. Il18r -/- and Il18bp transgenic mice
had phenotypes similar to that of Il18 -/- mice. Netea et al. (2006)
concluded that IL18 has an important role in homeostasis of energy
intake and insulin sensitivity.
*FIELD* RF
1. Blankenberg, S.; Luc, G.; Ducimetiere, P.; Arveiler, D.; Ferrieres,
J.; Amouyel, P.; Evans, A.; Cambien, F.; Tiret, L.: Interleukin-18
and the risk of coronary heart disease in European men: the prospective
epidemiological study of myocardial infarction (PRIME). Circulation 108:
2453-2459, 2003.
2. Blankenberg, S.; Tiret, L.; Bickel, C.; Peetz, D.; Cambien, F.;
Meyer, J.; Rupprecht, H. J.: Interleukin-18 is a strong predictor
of cardiovascular death in stable and unstable angina. Circulation 106:
24-30, 2002.
3. Bossu, P.; Neumann, D.; Del Giudice, E.; Ciaramella, A.; Gloaguen,
I.; Fantuzzi, G.; Dinarello, C. A.; Di Carlo, E.; Musiani, P.; Meroni,
P. L.; Caselli, G.; Ruggiero, P.; Boraschi, D.: IL-18 cDNA vaccination
protects mice from spontaneous lupus-like autoimmune disease. Proc.
Nat. Acad. Sci. 100: 14181-14186, 2003.
4. Corbaz, A.; ten Hove, T.; Herren, S.; Graber, P.; Schwartsburd,
B.; Belzer, I.; Harrison, J.; Plitz, T.; Kosco-Vilbois, M. H.; Kim,
S.-H.; Dinarello, C. A.; Novick, D.; van Deventer, S.; Chvatchko,
Y.: IL-18-binding protein expression by endothelial cells and macrophages
is up-regulated during active Crohn's disease. J. Immun. 168: 3608-3616,
2002.
5. Henao-Mejia, J.; Elinav, E.; Jin, C.; Hao, L.; Mehal, W. Z.; Strowig,
T.; Thaiss, C. A.; Kau, A. L.; Eisenbarth, S. C.; Jurczak, M. J.;
Camporez, J.-P.; Shulman, G. I.; Gordon, J. I.; Hoffman, H. M.; Flavell,
R. A.: Inflammasome-mediated dysbiosis regulates progression of NAFLD
and obesity. Nature 482: 179-185, 2012.
6. Huang, M. T.-H.; Mortensen, B. L.; Taxman, D. J.; Craven, R. R.;
Taft-Benz, S.; Kijek, T. M.; Fuller, J. R.; Davis, B. K.; Allen, I.
C.; Brickey, W. J.; Gris, D.; Wen, H.; Kawula, T. H.; Ting, J. P.-Y.
: Deletion of ripA alleviates suppression of the inflammasome and
MAPK by Francisella tularensis. J. Immun. 185: 5476-5485, 2010.
7. Konishi, H.; Tsutsui, H.; Murakami, T.; Yumikura-Futatsugi, S.;
Yamanaka, K.; Tanaka, M.; Iwakura, Y.; Suzuki, N.; Takeda, K.; Akira,
S.; Nakanishi, K.; Mizutani, H.: IL-18 contributes to the spontaneous
development of atopic dermatitis-like inflammatory skin lesion independently
of IgE/stat6 under specific pathogen-free conditions. Proc. Nat.
Acad. Sci. 99: 11340-11345, 2002.
8. Lee, C.-C.; Lin, W.-Y.; Wan, L.; Tsai, Y.; Lin, Y.-J.; Tsai, C.-H.;
Huang, C.-M.; Tsai, F.-J.: Interleukin-18 gene polymorphism, but
not interleukin-2 gene polymorphism, is associated with rheumatoid
arthritis. Immunogenetics 59: 433-439, 2007.
9. Mallat, Z.; Corbaz, A.; Scoazec, A.; Besnard, S.; Leseche, G.;
Chvatchko, Y.; Tedgui, A.: Expression of interleukin-18 in human
atherosclerotic plaques and relation to plaque instability. Circulation 104:
1598-1603, 2001.
10. Netea, M. G.; Joosten, L. A. B.; Lewis, E.; Jensen, D. R.; Voshol,
P. J.; Kullberg, B. J.; Tack, C. J.; van Krieken, H.; Kim, S.-H.;
Stalenhoef, A. F.; van de Loo, F. A.; Verschueren, I.; Pulawa, L.;
Akira, S.; Eckel, R. H.; Dinarello, C. A.; van den Berg, W.; van der
Meer, J. W. M.: Deficiency of interleukin-18 in mice leads to hyperphagia,
obesity and insulin resistance. Nature Med. 12: 650-656, 2006.
11. Nolan, K. F.; Greaves, D. R.; Waldmann, H.: The human interleukin
18 gene IL18 maps to 11q22.2-q22.3, closely linked to the DRD2 gene
locus and distinct from mapped IDDM loci. Genomics 51: 161-163,
1998.
12. Okamoto, I.; Kohno, K.; Tanimoto, T.; Iwaki, K.; Ishihara, T.;
Akamatsu, S.; Ikegami, H.; Kurimoto, M.: IL-18 prevents the development
of chronic graft-versus-host disease in mice. J. Immun. 164: 6067-6074,
2000.
13. Okamura, H.; Tsutsui, H.; Komatsu, T.; Yutsudo, M.; Hakura, A.;
Tanimoto, T.; Torigoe, K.; Okura, T.; Nukada, Y.; Hattori, K.; Akita,
K.; Namba, M.; Tanabe, F.; Konishi, K.; Fukuda, S.; Kurimoto, M.:
Cloning of a new cytokine that induces IFN-gamma production by T cells. Nature 378:
88-91, 1995.
14. Pizarro, T. T.; Michie, M. H.; Bentz, M.; Woraratanadharm, J.;
Smith, M. F., Jr.; Foley, E.; Moskaluk, C. A.; Bickston, S. J.; Cominelli,
F.: IL-18, a novel immunoregulatory cytokine, is up-regulated in
Crohn's disease: expression and localization in intestinal mucosal
cells. J. Immun. 162: 6829-6835, 1999.
15. Reddy, P.; Teshima, T.; Kukuruga, M.; Ordemann, R.; Liu, C.; Lowler,
K.; Ferrara, J. L. M.: Interleukin-18 regulates acute graft-versus-host
disease by enhancing Fas-mediated donor T cell apoptosis. J. Exp.
Med. 194: 1433-1440, 2001.
16. Rothe, H.; Jenkins, N. A.; Copeland, N. G.; Kolb, H.: Active
stage of autoimmune diabetes is associated with the expression of
a novel cytokine, IGIF, which is located near Idd2. J. Clin. Invest. 99:
469-474, 1997.
17. Sanchez, E.; Palomino-Morales, R. J.; Ortego-Centeno, N.; Jimenez-Alonso,
J.; Gonzalez-Gay, M. A.; Lopez-Nevot, M. A.; Sanchez-Roman, J.; de
Ramon, E.; Gonzalez-Escribano, M. F.; Pons-Estel, B. A.; D'Alfonso,
S.; Sebastiani, G. D.; Italian Collaborative Group; Alarcon-Riquelme,
M. E.; Martin, J.: Identification of a new putative functional IL18
gene variant through an association study in systemic lupus erythematosus. Hum.
Molec. Genet. 18: 3739-3748, 2009.
18. Sarvetnick, N.: IFN-gamma, IGIF, and IDDM. (Editorial) J. Clin.
Invest. 99: 371-372, 1997.
19. Shida, K.; Shiratori, I.; Matsumoto, M.; Fukumori, Y.; Matsuhisa,
A.; Kikkawa, S.; Tsuji, S.; Okamura, H.; Toyoshima, K.; Seya, T.:
An alternative form of IL-18 in human blood plasma: complex formation
with IgM defined by monoclonal antibodies. J. Immun. 166: 6671-6679,
2001.
20. Sugawara, S.; Uehara, A.; Nochi, T.; Yamaguchi, T.; Ueda, H.;
Sugiyama, A.; Hanzawa, K.; Kumagai, K.; Okamura, H.; Takada, H.:
Neutrophil proteinase 3-mediated induction of bioactive IL-18 secretion
by human oral epithelial cells. J. Immun. 167: 6568-6575, 2001.
21. ten Hove, T.; Corbaz, A.; Amitai, H.; Aloni, S.; Belzer, I.; Graber,
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*FIELD* CN
Ada Hamosh - updated: 3/7/2012
Paul J. Converse - updated: 2/9/2011
George E. Tiller - updated: 7/8/2010
Paul J. Converse - updated: 6/26/2008
Paul J. Converse - updated: 7/20/2006
Paul J. Converse - updated: 4/11/2006
Marla J. F. O'Neill - updated: 4/6/2006
Marla J. F. O'Neill - updated: 2/15/2006
Victor A. McKusick - updated: 12/3/2004
Victor A. McKusick - updated: 10/9/2002
Paul J. Converse - updated: 5/8/2002
Paul J. Converse - updated: 2/20/2002
Paul J. Converse - updated: 1/17/2002
Paul J. Converse - updated: 10/17/2001
Victor A. McKusick - updated: 2/9/2000
Carol A. Bocchini - updated: 4/4/1999
Victor A. McKusick - updated: 3/16/1997
*FIELD* CD
Victor A. McKusick: 12/8/1995
*FIELD* ED
alopez: 03/09/2012
terry: 3/7/2012
mgross: 12/16/2011
mgross: 2/9/2011
wwang: 7/23/2010
terry: 7/8/2010
carol: 8/14/2008
mgross: 7/8/2008
terry: 6/26/2008
mgross: 8/4/2006
terry: 7/20/2006
mgross: 5/2/2006
terry: 4/11/2006
wwang: 4/7/2006
terry: 4/6/2006
carol: 2/15/2006
tkritzer: 12/8/2004
terry: 12/3/2004
tkritzer: 7/15/2003
tkritzer: 10/9/2002
mgross: 5/8/2002
mgross: 2/20/2002
mgross: 1/17/2002
mgross: 10/17/2001
mgross: 3/1/2000
terry: 2/9/2000
mgross: 4/6/1999
carol: 4/4/1999
psherman: 1/5/1999
alopez: 6/19/1998
mark: 7/30/1997
alopez: 7/24/1997
mark: 3/16/1997
terry: 3/10/1997
mark: 12/8/1995