Full text data of IL6R
IL6R
[Confidence: high (a blood group or CD marker)]
Interleukin-6 receptor subunit alpha; IL-6 receptor subunit alpha; IL-6R subunit alpha; IL-6R-alpha; IL-6RA (IL-6R 1; Membrane glycoprotein 80; gp80; CD126; Flags: Precursor)
Interleukin-6 receptor subunit alpha; IL-6 receptor subunit alpha; IL-6R subunit alpha; IL-6R-alpha; IL-6RA (IL-6R 1; Membrane glycoprotein 80; gp80; CD126; Flags: Precursor)
UniProt
P08887
ID IL6RA_HUMAN Reviewed; 468 AA.
AC P08887; A8KAE8; B2R6V4; Q16202; Q53EQ7; Q5FWG2; Q5VZ23;
DT 01-NOV-1988, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-NOV-1988, sequence version 1.
DT 22-JAN-2014, entry version 166.
DE RecName: Full=Interleukin-6 receptor subunit alpha;
DE Short=IL-6 receptor subunit alpha;
DE Short=IL-6R subunit alpha;
DE Short=IL-6R-alpha;
DE Short=IL-6RA;
DE AltName: Full=IL-6R 1;
DE AltName: Full=Membrane glycoprotein 80;
DE Short=gp80;
DE AltName: CD_antigen=CD126;
DE Flags: Precursor;
GN Name=IL6R;
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).
RX PubMed=3136546; DOI=10.1126/science.3136546;
RA Yamasaki K., Taga T., Hirata Y., Yawata H., Kawanishi Y., Seed B.,
RA Taniguchi T., Hirano T., Kishimoto T.;
RT "Cloning and expression of the human interleukin-6 (BSF-2/IFN beta 2)
RT receptor.";
RL Science 241:825-828(1988).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RA Yamasaki K., Taga T., Hirata Y., Yawata H., Kawanishi Y., Seed B.,
RA Taniguchi T., Hirano T., Kishimoto T.;
RT "Molecular structure of interleukin 6 receptor.";
RL Proc. Jpn. Acad., B, Phys. Biol. Sci. 64:209-211(1988).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=1872801;
RA Schooltink H., Stoyan T., Lenz D., Schmitz H., Hirano T.,
RA Kishimoto T., Heinrich P.C., Rose-John S.;
RT "Structural and functional studies on the human hepatic interleukin-6
RT receptor. Molecular cloning and overexpression in HepG2 cells.";
RL Biochem. J. 277:659-664(1991).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2), AND VARIANT
RP ALA-358.
RC TISSUE=Trachea;
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 [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Kidney;
RA Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S.;
RL Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16710414; DOI=10.1038/nature04727;
RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D.,
RA Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A.,
RA Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F.,
RA McDonald L., Evans R., Phillips K., Atkinson A., Cooper R., Jones C.,
RA Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P.,
RA Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K.,
RA Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G.,
RA Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D.,
RA Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G.,
RA Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J.,
RA Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R.,
RA Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D.,
RA Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G.,
RA Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M.,
RA Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J.,
RA Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M.,
RA Loveland J., Lovell J., Lush M.J., Lyne R., Martin S.,
RA Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S.,
RA Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C.,
RA Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z.,
RA Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E.,
RA Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A.,
RA Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R.,
RA Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V.,
RA Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence and biological annotation of human chromosome 1.";
RL Nature 441:315-321(2006).
RN [7]
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 (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Lymph;
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 313-365 (ISOFORM 2).
RX PubMed=8056053; DOI=10.1002/eji.1830240837;
RA Horiuchi S., Koyanagi Y., Zhou Y., Miyamoto H., Tanaka Y., Waki M.,
RA Matsumoto A., Yamamoto M., Yamamoto N.;
RT "Soluble interleukin-6 receptors released from T cell or
RT granulocyte/macrophage cell lines and human peripheral blood
RT mononuclear cells are generated through an alternative splicing
RT mechanism.";
RL Eur. J. Immunol. 24:1945-1948(1994).
RN [10]
RP PARTIAL PROTEIN SEQUENCE, GLYCOSYLATION AT ASN-55; ASN-93 AND ASN-221,
RP LACK OF GLYCOSYLATION AT ASN-245, AND DISULFIDE BONDS.
RX PubMed=10066782; DOI=10.1074/jbc.274.11.7207;
RA Cole A.R., Hall N.E., Treutlein H.R., Eddes J.S., Reid G.E.,
RA Moritz R.L., Simpson R.J.;
RT "Disulfide bond structure and N-glycosylation sites of the
RT extracellular domain of the human interleukin-6 receptor.";
RL J. Biol. Chem. 274:7207-7215(1999).
RN [11]
RP PROTEIN SEQUENCE OF 20-49, AND SUBCELLULAR LOCATION.
RX PubMed=2529343; DOI=10.1084/jem.170.4.1409;
RA Novick D., Engelmann H., Wallach D., Rubinstein M.;
RT "Soluble cytokine receptors are present in normal human urine.";
RL J. Exp. Med. 170:1409-1414(1989).
RN [12]
RP MUTAGENESIS.
RX PubMed=8467812;
RA Yawata H., Yasukawa K., Natsuka S., Murakami M., Yamasaki K., Hibi M.,
RA Taga T., Kishimoto T.;
RT "Structure-function analysis of human IL-6 receptor: dissociation of
RT amino acid residues required for IL-6-binding and for IL-6 signal
RT transduction through gp130.";
RL EMBO J. 12:1705-1712(1993).
RN [13]
RP FUNCTION.
RX PubMed=11017875;
RA Martens A.S., Bode J.G., Heinrich P.C., Graeve L.;
RT "The cytoplasmic domain of the interleukin-6 receptor gp80 mediates
RT its basolateral sorting in polarized Madin-Darby canine kidney
RT cells.";
RL J. Cell Sci. 113:3593-3602(2000).
RN [14]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=16270750; DOI=10.1016/j.ejcb.2005.06.001;
RA Buk D.M., Renner O., Graeve L.;
RT "Increased association with detergent-resistant membranes/lipid rafts
RT of apically targeted mutants of the interleukin-6 receptor gp80.";
RL Eur. J. Cell Biol. 84:819-831(2005).
RN [15]
RP X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) OF 20-344.
RX PubMed=12461182; DOI=10.1073/pnas.232432399;
RA Varghese J.N., Moritz R.L., Lou M.-Z., Van Donkelaar A., Ji H.,
RA Ivancic N., Branson K.M., Hall N.E., Simpson R.J.;
RT "Structure of the extracellular domains of the human interleukin-6
RT receptor alpha-chain.";
RL Proc. Natl. Acad. Sci. U.S.A. 99:15959-15964(2002).
RN [16]
RP X-RAY CRYSTALLOGRAPHY (3.65 ANGSTROMS) OF 115-315.
RX PubMed=12829785; DOI=10.1126/science.1083901;
RA Boulanger M.J., Chow D.-C., Brevnova E.E., Garcia K.C.;
RT "Hexameric structure and assembly of the interleukin-6/IL-6 alpha-
RT receptor/gp130 complex.";
RL Science 300:2101-2104(2003).
RN [17]
RP POLYMORPHISM, VARIANT ALA-358, AND ASSOCIATION OF VARIANT ALA-358 WITH
RP IL6 AND SOLUBLE IL6R SERUM LEVELS.
RX PubMed=17357077; DOI=10.1086/513206;
RG Health, Aging and Body Composition (Health ABC) Study;
RA Reich D., Patterson N., Ramesh V., De Jager P.L., McDonald G.J.,
RA Tandon A., Choy E., Hu D., Tamraz B., Pawlikowska L., Wassel-Fyr C.,
RA Huntsman S., Waliszewska A., Rossin E., Li R., Garcia M., Reiner A.,
RA Ferrell R., Cummings S., Kwok P.Y., Harris T., Zmuda J.M., Ziv E.;
RT "Admixture mapping of an allele affecting interleukin 6 soluble
RT receptor and interleukin 6 levels.";
RL Am. J. Hum. Genet. 80:716-726(2007).
CC -!- FUNCTION: Part of the receptor for interleukin 6. Binds to IL6
CC with low affinity, but does not transduce a signal. Signal
CC activation necessitate an association with IL6ST. Activation may
CC lead to the regulation of the immune response, acute-phase
CC reactions and hematopoiesis.
CC -!- FUNCTION: Low concentration of a soluble form of IL6 receptor acts
CC as an agonist of IL6 activity.
CC -!- SUBUNIT: Hexamer of two molecules each of IL6, IL6R and IL6ST.
CC -!- SUBCELLULAR LOCATION: Isoform 1: Basolateral cell membrane;
CC Single-pass type I membrane protein.
CC -!- SUBCELLULAR LOCATION: Isoform 2: Secreted.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1; Synonyms=Long;
CC IsoId=P08887-1; Sequence=Displayed;
CC Name=2; Synonyms=Short;
CC IsoId=P08887-2; Sequence=VSP_001682, VSP_001683;
CC -!- TISSUE SPECIFICITY: Isoform 2 is expressed in peripheral blood
CC mononuclear cells and weakly found in urine and serum.
CC -!- DOMAIN: The two fibronectin type-III-like domains, contained in
CC the N-terminal part, form together a cytokine-binding domain.
CC -!- DOMAIN: The WSXWS motif appears to be necessary for proper protein
CC folding and thereby efficient intracellular transport and cell-
CC surface receptor binding.
CC -!- PTM: A short soluble form may also be released from the membrane
CC by proteolysis.
CC -!- POLYMORPHISM: Genetic variations in IL6R determine soluble IL6R
CC serum levels [MIM:614689].
CC -!- POLYMORPHISM: Genetic variations in IL6R define the IL6 serum
CC level quantitative trait locus [MIM:614752].
CC -!- SIMILARITY: Belongs to the type I cytokine receptor family. Type 3
CC subfamily.
CC -!- SIMILARITY: Contains 2 fibronectin type-III domains.
CC -!- SIMILARITY: Contains 1 Ig-like C2-type (immunoglobulin-like)
CC domain.
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; X12830; CAA31312.1; -; mRNA.
DR EMBL; X58298; CAA41231.1; -; mRNA.
DR EMBL; AK293013; BAF85702.1; -; mRNA.
DR EMBL; AK312730; BAG35601.1; -; mRNA.
DR EMBL; AK223582; BAD97302.1; -; mRNA.
DR EMBL; AL162591; CAH72853.1; -; Genomic_DNA.
DR EMBL; CH471121; EAW53200.1; -; Genomic_DNA.
DR EMBL; BC089410; AAH89410.1; -; mRNA.
DR EMBL; S72848; AAC60635.1; -; mRNA.
DR PIR; A41242; A41242.
DR RefSeq; NP_000556.1; NM_000565.3.
DR RefSeq; NP_001193795.1; NM_001206866.1.
DR RefSeq; NP_852004.1; NM_181359.2.
DR UniGene; Hs.135087; -.
DR PDB; 1N26; X-ray; 2.40 A; A=20-344.
DR PDB; 1N2Q; Model; -; C/D=20-344.
DR PDB; 1P9M; X-ray; 3.65 A; C=115-315.
DR PDB; 2ARW; NMR; -; A=212-336.
DR PDBsum; 1N26; -.
DR PDBsum; 1N2Q; -.
DR PDBsum; 1P9M; -.
DR PDBsum; 2ARW; -.
DR ProteinModelPortal; P08887; -.
DR SMR; P08887; 20-318.
DR DIP; DIP-162N; -.
DR DIP; DIP-3777N; -.
DR IntAct; P08887; 3.
DR MINT; MINT-190110; -.
DR STRING; 9606.ENSP00000357470; -.
DR ChEMBL; CHEMBL2364155; -.
DR PhosphoSite; P08887; -.
DR DMDM; 124343; -.
DR PaxDb; P08887; -.
DR PRIDE; P08887; -.
DR DNASU; 3570; -.
DR Ensembl; ENST00000344086; ENSP00000340589; ENSG00000160712.
DR Ensembl; ENST00000368485; ENSP00000357470; ENSG00000160712.
DR GeneID; 3570; -.
DR KEGG; hsa:3570; -.
DR UCSC; uc001fez.2; human.
DR CTD; 3570; -.
DR GeneCards; GC01P154377; -.
DR HGNC; HGNC:6019; IL6R.
DR MIM; 147880; gene.
DR MIM; 614689; phenotype.
DR MIM; 614752; phenotype.
DR neXtProt; NX_P08887; -.
DR PharmGKB; PA29835; -.
DR eggNOG; NOG47227; -.
DR HOVERGEN; HBG052118; -.
DR InParanoid; P08887; -.
DR KO; K05055; -.
DR OMA; CQLAVPE; -.
DR OrthoDB; EOG71CFM2; -.
DR PhylomeDB; P08887; -.
DR Reactome; REACT_6900; Immune System.
DR SignaLink; P08887; -.
DR EvolutionaryTrace; P08887; -.
DR GeneWiki; Interleukin-6_receptor; -.
DR GenomeRNAi; 3570; -.
DR NextBio; 13954; -.
DR PMAP-CutDB; P08887; -.
DR PRO; PR:P08887; -.
DR ArrayExpress; P08887; -.
DR Bgee; P08887; -.
DR CleanEx; HS_IL6R; -.
DR Genevestigator; P08887; -.
DR GO; GO:0016324; C:apical plasma membrane; IDA:BHF-UCL.
DR GO; GO:0016323; C:basolateral plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0009986; C:cell surface; IEA:Ensembl.
DR GO; GO:0005576; C:extracellular region; IDA:UniProtKB.
DR GO; GO:0005615; C:extracellular space; IDA:BHF-UCL.
DR GO; GO:0005896; C:interleukin-6 receptor complex; IDA:BHF-UCL.
DR GO; GO:0004915; F:interleukin-6 receptor activity; IEA:Ensembl.
DR GO; GO:0006953; P:acute-phase response; TAS:BHF-UCL.
DR GO; GO:0070120; P:ciliary neurotrophic factor-mediated signaling pathway; IMP:BHF-UCL.
DR GO; GO:0050829; P:defense response to Gram-negative bacterium; IEP:BHF-UCL.
DR GO; GO:0050830; P:defense response to Gram-positive bacterium; IEP:BHF-UCL.
DR GO; GO:0031018; P:endocrine pancreas development; IMP:BHF-UCL.
DR GO; GO:0097191; P:extrinsic apoptotic signaling pathway; TAS:BHF-UCL.
DR GO; GO:0002384; P:hepatic immune response; TAS:BHF-UCL.
DR GO; GO:0070102; P:interleukin-6-mediated signaling pathway; IMP:BHF-UCL.
DR GO; GO:0002548; P:monocyte chemotaxis; IC:BHF-UCL.
DR GO; GO:0032966; P:negative regulation of collagen biosynthetic process; IDA:BHF-UCL.
DR GO; GO:0032717; P:negative regulation of interleukin-8 production; IEP:BHF-UCL.
DR GO; GO:0002446; P:neutrophil mediated immunity; IC:BHF-UCL.
DR GO; GO:0010536; P:positive regulation of activation of Janus kinase activity; IDA:BHF-UCL.
DR GO; GO:0032722; P:positive regulation of chemokine production; IDA:BHF-UCL.
DR GO; GO:0032755; P:positive regulation of interleukin-6 production; IDA:BHF-UCL.
DR GO; GO:0002690; P:positive regulation of leukocyte chemotaxis; IC:BHF-UCL.
DR GO; GO:0043410; P:positive regulation of MAPK cascade; IDA:BHF-UCL.
DR GO; GO:0045669; P:positive regulation of osteoblast differentiation; TAS:BHF-UCL.
DR GO; GO:0048661; P:positive regulation of smooth muscle cell proliferation; IDA:BHF-UCL.
DR GO; GO:0042517; P:positive regulation of tyrosine phosphorylation of Stat3 protein; IMP:BHF-UCL.
DR Gene3D; 2.60.40.10; -; 3.
DR InterPro; IPR003961; Fibronectin_type3.
DR InterPro; IPR003530; Hematopoietin_rcpt_L_F3_CS.
DR InterPro; IPR007110; Ig-like_dom.
DR InterPro; IPR013783; Ig-like_fold.
DR InterPro; IPR003598; Ig_sub2.
DR InterPro; IPR015321; IL-6_rcpt_alpha-bd.
DR Pfam; PF09240; IL6Ra-bind; 1.
DR SMART; SM00060; FN3; 1.
DR SMART; SM00408; IGc2; 1.
DR SUPFAM; SSF49265; SSF49265; 2.
DR PROSITE; PS50853; FN3; 2.
DR PROSITE; PS01354; HEMATOPO_REC_L_F3; 1.
DR PROSITE; PS50835; IG_LIKE; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Cell membrane; Complete proteome;
KW Direct protein sequencing; Disulfide bond; Glycoprotein;
KW Immunoglobulin domain; Membrane; Polymorphism; Receptor;
KW Reference proteome; Repeat; Secreted; Signal; Transmembrane;
KW Transmembrane helix.
FT SIGNAL 1 19
FT CHAIN 20 468 Interleukin-6 receptor subunit alpha.
FT /FTId=PRO_0000010895.
FT TOPO_DOM 20 365 Extracellular (Potential).
FT TRANSMEM 366 386 Helical; (Potential).
FT TOPO_DOM 387 468 Cytoplasmic (Potential).
FT DOMAIN 26 112 Ig-like C2-type.
FT DOMAIN 113 217 Fibronectin type-III 1.
FT DOMAIN 218 316 Fibronectin type-III 2.
FT MOTIF 303 307 WSXWS motif.
FT SITE 245 245 Not glycosylated.
FT CARBOHYD 55 55 N-linked (GlcNAc...).
FT CARBOHYD 93 93 N-linked (GlcNAc...).
FT CARBOHYD 221 221 N-linked (GlcNAc...).
FT DISULFID 25 193
FT DISULFID 47 96
FT DISULFID 121 132
FT DISULFID 165 176
FT VAR_SEQ 356 365 VQDSSSVPLP -> GSRRRGSCGL (in isoform 2).
FT /FTId=VSP_001682.
FT VAR_SEQ 366 468 Missing (in isoform 2).
FT /FTId=VSP_001683.
FT VARIANT 358 358 D -> A (significantly associated with
FT circulating levels of IL6 and soluble
FT IL6R; dbSNP:rs2228145).
FT /FTId=VAR_021995.
FT VARIANT 385 385 V -> I (in dbSNP:rs28730736).
FT /FTId=VAR_049166.
FT MUTAGEN 121 121 C->S: Complete loss of ligand-binding.
FT MUTAGEN 122 122 F->A: No change of ligand-binding and IL6
FT signaling.
FT MUTAGEN 132 132 C->A: Complete loss of ligand-binding.
FT MUTAGEN 134 134 W->L: Complete loss of ligand-binding.
FT MUTAGEN 140 140 P->G: No change of ligand-binding and IL6
FT signaling.
FT MUTAGEN 153 153 F->L: No change of ligand-binding and IL6
FT signaling.
FT MUTAGEN 165 165 C->L: Complete loss of ligand-binding.
FT MUTAGEN 174 174 F->L: No change of ligand-binding and IL6
FT signaling.
FT MUTAGEN 176 176 C->A: Complete loss of ligand-binding.
FT MUTAGEN 184 184 D->T: 30% decrease of ligand-binding and
FT IL6 signaling.
FT MUTAGEN 190 190 V->G: 80% decrease of ligand-binding and
FT no IL6 signaling.
FT MUTAGEN 193 193 C->D: Complete loss of ligand-binding.
FT MUTAGEN 211 211 C->A: No change of ligand-binding and IL6
FT signaling.
FT MUTAGEN 217 217 D->V: Complete loss of ligand-binding.
FT MUTAGEN 232 232 R->S: 30% decrease of ligand-binding and
FT IL6 signaling.
FT MUTAGEN 233 233 W->Q: 30% decrease of ligand-binding and
FT increase of IL6 signaling.
FT MUTAGEN 254 254 E->A: 50% decrease of ligand-binding and
FT IL6 signaling.
FT MUTAGEN 277 277 C->D: 30% increase of ligand-binding and
FT 100% increase in IL6 signaling.
FT MUTAGEN 278 278 V->N: 50% Decrease of ligand-binding and
FT 50% increase in IL6 signaling.
FT MUTAGEN 279 279 I->D: Complete loss of ligand-binding.
FT MUTAGEN 280 280 H->I: No change of ligand-binding and no
FT IL6 signaling.
FT MUTAGEN 281 281 D->G: 70% decrease of ligand-binding and
FT no IL6 signaling.
FT MUTAGEN 285 285 G->D: 80% decrease of ligand-binding and
FT no IL6 signaling.
FT MUTAGEN 291 291 Q->K: Complete loss of ligand-binding.
FT MUTAGEN 293 293 R->G: Complete loss of ligand-binding.
FT CONFLICT 210 210 G -> D (in Ref. 5; BAD97302).
FT STRAND 34 37
FT STRAND 43 46
FT STRAND 56 63
FT STRAND 65 68
FT STRAND 72 83
FT HELIX 88 90
FT STRAND 92 101
FT STRAND 105 110
FT STRAND 120 125
FT STRAND 130 134
FT STRAND 145 157
FT STRAND 159 168
FT TURN 169 172
FT STRAND 173 178
FT STRAND 187 196
FT STRAND 199 202
FT STRAND 206 209
FT TURN 210 212
FT STRAND 220 226
FT STRAND 234 239
FT STRAND 247 249
FT STRAND 251 259
FT STRAND 266 269
FT HELIX 271 273
FT STRAND 275 281
FT STRAND 288 296
FT TURN 297 299
FT STRAND 310 312
SQ SEQUENCE 468 AA; 51548 MW; 62AA239FA14F1B8B CRC64;
MLAVGCALLA ALLAAPGAAL APRRCPAQEV ARGVLTSLPG DSVTLTCPGV EPEDNATVHW
VLRKPAAGSH PSRWAGMGRR LLLRSVQLHD SGNYSCYRAG RPAGTVHLLV DVPPEEPQLS
CFRKSPLSNV VCEWGPRSTP SLTTKAVLLV RKFQNSPAED FQEPCQYSQE SQKFSCQLAV
PEGDSSFYIV SMCVASSVGS KFSKTQTFQG CGILQPDPPA NITVTAVARN PRWLSVTWQD
PHSWNSSFYR LRFELRYRAE RSKTFTTWMV KDLQHHCVIH DAWSGLRHVV QLRAQEEFGQ
GEWSEWSPEA MGTPWTESRS PPAENEVSTP MQALTTNKDD DNILFRDSAN ATSLPVQDSS
SVPLPTFLVA GGSLAFGTLL CIAIVLRFKK TWKLRALKEG KTSMHPPYSL GQLVPERPRP
TPVLVPLISP PVSPSSLGSD NTSSHNRPDA RDPRSPYDIS NTDYFFPR
//
ID IL6RA_HUMAN Reviewed; 468 AA.
AC P08887; A8KAE8; B2R6V4; Q16202; Q53EQ7; Q5FWG2; Q5VZ23;
DT 01-NOV-1988, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-NOV-1988, sequence version 1.
DT 22-JAN-2014, entry version 166.
DE RecName: Full=Interleukin-6 receptor subunit alpha;
DE Short=IL-6 receptor subunit alpha;
DE Short=IL-6R subunit alpha;
DE Short=IL-6R-alpha;
DE Short=IL-6RA;
DE AltName: Full=IL-6R 1;
DE AltName: Full=Membrane glycoprotein 80;
DE Short=gp80;
DE AltName: CD_antigen=CD126;
DE Flags: Precursor;
GN Name=IL6R;
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).
RX PubMed=3136546; DOI=10.1126/science.3136546;
RA Yamasaki K., Taga T., Hirata Y., Yawata H., Kawanishi Y., Seed B.,
RA Taniguchi T., Hirano T., Kishimoto T.;
RT "Cloning and expression of the human interleukin-6 (BSF-2/IFN beta 2)
RT receptor.";
RL Science 241:825-828(1988).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RA Yamasaki K., Taga T., Hirata Y., Yawata H., Kawanishi Y., Seed B.,
RA Taniguchi T., Hirano T., Kishimoto T.;
RT "Molecular structure of interleukin 6 receptor.";
RL Proc. Jpn. Acad., B, Phys. Biol. Sci. 64:209-211(1988).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=1872801;
RA Schooltink H., Stoyan T., Lenz D., Schmitz H., Hirano T.,
RA Kishimoto T., Heinrich P.C., Rose-John S.;
RT "Structural and functional studies on the human hepatic interleukin-6
RT receptor. Molecular cloning and overexpression in HepG2 cells.";
RL Biochem. J. 277:659-664(1991).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2), AND VARIANT
RP ALA-358.
RC TISSUE=Trachea;
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 [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Kidney;
RA Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S.;
RL Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16710414; DOI=10.1038/nature04727;
RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D.,
RA Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A.,
RA Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F.,
RA McDonald L., Evans R., Phillips K., Atkinson A., Cooper R., Jones C.,
RA Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P.,
RA Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K.,
RA Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G.,
RA Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D.,
RA Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G.,
RA Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J.,
RA Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R.,
RA Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D.,
RA Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G.,
RA Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M.,
RA Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J.,
RA Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M.,
RA Loveland J., Lovell J., Lush M.J., Lyne R., Martin S.,
RA Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S.,
RA Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C.,
RA Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z.,
RA Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E.,
RA Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A.,
RA Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R.,
RA Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V.,
RA Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence and biological annotation of human chromosome 1.";
RL Nature 441:315-321(2006).
RN [7]
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 (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Lymph;
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 313-365 (ISOFORM 2).
RX PubMed=8056053; DOI=10.1002/eji.1830240837;
RA Horiuchi S., Koyanagi Y., Zhou Y., Miyamoto H., Tanaka Y., Waki M.,
RA Matsumoto A., Yamamoto M., Yamamoto N.;
RT "Soluble interleukin-6 receptors released from T cell or
RT granulocyte/macrophage cell lines and human peripheral blood
RT mononuclear cells are generated through an alternative splicing
RT mechanism.";
RL Eur. J. Immunol. 24:1945-1948(1994).
RN [10]
RP PARTIAL PROTEIN SEQUENCE, GLYCOSYLATION AT ASN-55; ASN-93 AND ASN-221,
RP LACK OF GLYCOSYLATION AT ASN-245, AND DISULFIDE BONDS.
RX PubMed=10066782; DOI=10.1074/jbc.274.11.7207;
RA Cole A.R., Hall N.E., Treutlein H.R., Eddes J.S., Reid G.E.,
RA Moritz R.L., Simpson R.J.;
RT "Disulfide bond structure and N-glycosylation sites of the
RT extracellular domain of the human interleukin-6 receptor.";
RL J. Biol. Chem. 274:7207-7215(1999).
RN [11]
RP PROTEIN SEQUENCE OF 20-49, AND SUBCELLULAR LOCATION.
RX PubMed=2529343; DOI=10.1084/jem.170.4.1409;
RA Novick D., Engelmann H., Wallach D., Rubinstein M.;
RT "Soluble cytokine receptors are present in normal human urine.";
RL J. Exp. Med. 170:1409-1414(1989).
RN [12]
RP MUTAGENESIS.
RX PubMed=8467812;
RA Yawata H., Yasukawa K., Natsuka S., Murakami M., Yamasaki K., Hibi M.,
RA Taga T., Kishimoto T.;
RT "Structure-function analysis of human IL-6 receptor: dissociation of
RT amino acid residues required for IL-6-binding and for IL-6 signal
RT transduction through gp130.";
RL EMBO J. 12:1705-1712(1993).
RN [13]
RP FUNCTION.
RX PubMed=11017875;
RA Martens A.S., Bode J.G., Heinrich P.C., Graeve L.;
RT "The cytoplasmic domain of the interleukin-6 receptor gp80 mediates
RT its basolateral sorting in polarized Madin-Darby canine kidney
RT cells.";
RL J. Cell Sci. 113:3593-3602(2000).
RN [14]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=16270750; DOI=10.1016/j.ejcb.2005.06.001;
RA Buk D.M., Renner O., Graeve L.;
RT "Increased association with detergent-resistant membranes/lipid rafts
RT of apically targeted mutants of the interleukin-6 receptor gp80.";
RL Eur. J. Cell Biol. 84:819-831(2005).
RN [15]
RP X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) OF 20-344.
RX PubMed=12461182; DOI=10.1073/pnas.232432399;
RA Varghese J.N., Moritz R.L., Lou M.-Z., Van Donkelaar A., Ji H.,
RA Ivancic N., Branson K.M., Hall N.E., Simpson R.J.;
RT "Structure of the extracellular domains of the human interleukin-6
RT receptor alpha-chain.";
RL Proc. Natl. Acad. Sci. U.S.A. 99:15959-15964(2002).
RN [16]
RP X-RAY CRYSTALLOGRAPHY (3.65 ANGSTROMS) OF 115-315.
RX PubMed=12829785; DOI=10.1126/science.1083901;
RA Boulanger M.J., Chow D.-C., Brevnova E.E., Garcia K.C.;
RT "Hexameric structure and assembly of the interleukin-6/IL-6 alpha-
RT receptor/gp130 complex.";
RL Science 300:2101-2104(2003).
RN [17]
RP POLYMORPHISM, VARIANT ALA-358, AND ASSOCIATION OF VARIANT ALA-358 WITH
RP IL6 AND SOLUBLE IL6R SERUM LEVELS.
RX PubMed=17357077; DOI=10.1086/513206;
RG Health, Aging and Body Composition (Health ABC) Study;
RA Reich D., Patterson N., Ramesh V., De Jager P.L., McDonald G.J.,
RA Tandon A., Choy E., Hu D., Tamraz B., Pawlikowska L., Wassel-Fyr C.,
RA Huntsman S., Waliszewska A., Rossin E., Li R., Garcia M., Reiner A.,
RA Ferrell R., Cummings S., Kwok P.Y., Harris T., Zmuda J.M., Ziv E.;
RT "Admixture mapping of an allele affecting interleukin 6 soluble
RT receptor and interleukin 6 levels.";
RL Am. J. Hum. Genet. 80:716-726(2007).
CC -!- FUNCTION: Part of the receptor for interleukin 6. Binds to IL6
CC with low affinity, but does not transduce a signal. Signal
CC activation necessitate an association with IL6ST. Activation may
CC lead to the regulation of the immune response, acute-phase
CC reactions and hematopoiesis.
CC -!- FUNCTION: Low concentration of a soluble form of IL6 receptor acts
CC as an agonist of IL6 activity.
CC -!- SUBUNIT: Hexamer of two molecules each of IL6, IL6R and IL6ST.
CC -!- SUBCELLULAR LOCATION: Isoform 1: Basolateral cell membrane;
CC Single-pass type I membrane protein.
CC -!- SUBCELLULAR LOCATION: Isoform 2: Secreted.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1; Synonyms=Long;
CC IsoId=P08887-1; Sequence=Displayed;
CC Name=2; Synonyms=Short;
CC IsoId=P08887-2; Sequence=VSP_001682, VSP_001683;
CC -!- TISSUE SPECIFICITY: Isoform 2 is expressed in peripheral blood
CC mononuclear cells and weakly found in urine and serum.
CC -!- DOMAIN: The two fibronectin type-III-like domains, contained in
CC the N-terminal part, form together a cytokine-binding domain.
CC -!- DOMAIN: The WSXWS motif appears to be necessary for proper protein
CC folding and thereby efficient intracellular transport and cell-
CC surface receptor binding.
CC -!- PTM: A short soluble form may also be released from the membrane
CC by proteolysis.
CC -!- POLYMORPHISM: Genetic variations in IL6R determine soluble IL6R
CC serum levels [MIM:614689].
CC -!- POLYMORPHISM: Genetic variations in IL6R define the IL6 serum
CC level quantitative trait locus [MIM:614752].
CC -!- SIMILARITY: Belongs to the type I cytokine receptor family. Type 3
CC subfamily.
CC -!- SIMILARITY: Contains 2 fibronectin type-III domains.
CC -!- SIMILARITY: Contains 1 Ig-like C2-type (immunoglobulin-like)
CC domain.
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; X12830; CAA31312.1; -; mRNA.
DR EMBL; X58298; CAA41231.1; -; mRNA.
DR EMBL; AK293013; BAF85702.1; -; mRNA.
DR EMBL; AK312730; BAG35601.1; -; mRNA.
DR EMBL; AK223582; BAD97302.1; -; mRNA.
DR EMBL; AL162591; CAH72853.1; -; Genomic_DNA.
DR EMBL; CH471121; EAW53200.1; -; Genomic_DNA.
DR EMBL; BC089410; AAH89410.1; -; mRNA.
DR EMBL; S72848; AAC60635.1; -; mRNA.
DR PIR; A41242; A41242.
DR RefSeq; NP_000556.1; NM_000565.3.
DR RefSeq; NP_001193795.1; NM_001206866.1.
DR RefSeq; NP_852004.1; NM_181359.2.
DR UniGene; Hs.135087; -.
DR PDB; 1N26; X-ray; 2.40 A; A=20-344.
DR PDB; 1N2Q; Model; -; C/D=20-344.
DR PDB; 1P9M; X-ray; 3.65 A; C=115-315.
DR PDB; 2ARW; NMR; -; A=212-336.
DR PDBsum; 1N26; -.
DR PDBsum; 1N2Q; -.
DR PDBsum; 1P9M; -.
DR PDBsum; 2ARW; -.
DR ProteinModelPortal; P08887; -.
DR SMR; P08887; 20-318.
DR DIP; DIP-162N; -.
DR DIP; DIP-3777N; -.
DR IntAct; P08887; 3.
DR MINT; MINT-190110; -.
DR STRING; 9606.ENSP00000357470; -.
DR ChEMBL; CHEMBL2364155; -.
DR PhosphoSite; P08887; -.
DR DMDM; 124343; -.
DR PaxDb; P08887; -.
DR PRIDE; P08887; -.
DR DNASU; 3570; -.
DR Ensembl; ENST00000344086; ENSP00000340589; ENSG00000160712.
DR Ensembl; ENST00000368485; ENSP00000357470; ENSG00000160712.
DR GeneID; 3570; -.
DR KEGG; hsa:3570; -.
DR UCSC; uc001fez.2; human.
DR CTD; 3570; -.
DR GeneCards; GC01P154377; -.
DR HGNC; HGNC:6019; IL6R.
DR MIM; 147880; gene.
DR MIM; 614689; phenotype.
DR MIM; 614752; phenotype.
DR neXtProt; NX_P08887; -.
DR PharmGKB; PA29835; -.
DR eggNOG; NOG47227; -.
DR HOVERGEN; HBG052118; -.
DR InParanoid; P08887; -.
DR KO; K05055; -.
DR OMA; CQLAVPE; -.
DR OrthoDB; EOG71CFM2; -.
DR PhylomeDB; P08887; -.
DR Reactome; REACT_6900; Immune System.
DR SignaLink; P08887; -.
DR EvolutionaryTrace; P08887; -.
DR GeneWiki; Interleukin-6_receptor; -.
DR GenomeRNAi; 3570; -.
DR NextBio; 13954; -.
DR PMAP-CutDB; P08887; -.
DR PRO; PR:P08887; -.
DR ArrayExpress; P08887; -.
DR Bgee; P08887; -.
DR CleanEx; HS_IL6R; -.
DR Genevestigator; P08887; -.
DR GO; GO:0016324; C:apical plasma membrane; IDA:BHF-UCL.
DR GO; GO:0016323; C:basolateral plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0009986; C:cell surface; IEA:Ensembl.
DR GO; GO:0005576; C:extracellular region; IDA:UniProtKB.
DR GO; GO:0005615; C:extracellular space; IDA:BHF-UCL.
DR GO; GO:0005896; C:interleukin-6 receptor complex; IDA:BHF-UCL.
DR GO; GO:0004915; F:interleukin-6 receptor activity; IEA:Ensembl.
DR GO; GO:0006953; P:acute-phase response; TAS:BHF-UCL.
DR GO; GO:0070120; P:ciliary neurotrophic factor-mediated signaling pathway; IMP:BHF-UCL.
DR GO; GO:0050829; P:defense response to Gram-negative bacterium; IEP:BHF-UCL.
DR GO; GO:0050830; P:defense response to Gram-positive bacterium; IEP:BHF-UCL.
DR GO; GO:0031018; P:endocrine pancreas development; IMP:BHF-UCL.
DR GO; GO:0097191; P:extrinsic apoptotic signaling pathway; TAS:BHF-UCL.
DR GO; GO:0002384; P:hepatic immune response; TAS:BHF-UCL.
DR GO; GO:0070102; P:interleukin-6-mediated signaling pathway; IMP:BHF-UCL.
DR GO; GO:0002548; P:monocyte chemotaxis; IC:BHF-UCL.
DR GO; GO:0032966; P:negative regulation of collagen biosynthetic process; IDA:BHF-UCL.
DR GO; GO:0032717; P:negative regulation of interleukin-8 production; IEP:BHF-UCL.
DR GO; GO:0002446; P:neutrophil mediated immunity; IC:BHF-UCL.
DR GO; GO:0010536; P:positive regulation of activation of Janus kinase activity; IDA:BHF-UCL.
DR GO; GO:0032722; P:positive regulation of chemokine production; IDA:BHF-UCL.
DR GO; GO:0032755; P:positive regulation of interleukin-6 production; IDA:BHF-UCL.
DR GO; GO:0002690; P:positive regulation of leukocyte chemotaxis; IC:BHF-UCL.
DR GO; GO:0043410; P:positive regulation of MAPK cascade; IDA:BHF-UCL.
DR GO; GO:0045669; P:positive regulation of osteoblast differentiation; TAS:BHF-UCL.
DR GO; GO:0048661; P:positive regulation of smooth muscle cell proliferation; IDA:BHF-UCL.
DR GO; GO:0042517; P:positive regulation of tyrosine phosphorylation of Stat3 protein; IMP:BHF-UCL.
DR Gene3D; 2.60.40.10; -; 3.
DR InterPro; IPR003961; Fibronectin_type3.
DR InterPro; IPR003530; Hematopoietin_rcpt_L_F3_CS.
DR InterPro; IPR007110; Ig-like_dom.
DR InterPro; IPR013783; Ig-like_fold.
DR InterPro; IPR003598; Ig_sub2.
DR InterPro; IPR015321; IL-6_rcpt_alpha-bd.
DR Pfam; PF09240; IL6Ra-bind; 1.
DR SMART; SM00060; FN3; 1.
DR SMART; SM00408; IGc2; 1.
DR SUPFAM; SSF49265; SSF49265; 2.
DR PROSITE; PS50853; FN3; 2.
DR PROSITE; PS01354; HEMATOPO_REC_L_F3; 1.
DR PROSITE; PS50835; IG_LIKE; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Cell membrane; Complete proteome;
KW Direct protein sequencing; Disulfide bond; Glycoprotein;
KW Immunoglobulin domain; Membrane; Polymorphism; Receptor;
KW Reference proteome; Repeat; Secreted; Signal; Transmembrane;
KW Transmembrane helix.
FT SIGNAL 1 19
FT CHAIN 20 468 Interleukin-6 receptor subunit alpha.
FT /FTId=PRO_0000010895.
FT TOPO_DOM 20 365 Extracellular (Potential).
FT TRANSMEM 366 386 Helical; (Potential).
FT TOPO_DOM 387 468 Cytoplasmic (Potential).
FT DOMAIN 26 112 Ig-like C2-type.
FT DOMAIN 113 217 Fibronectin type-III 1.
FT DOMAIN 218 316 Fibronectin type-III 2.
FT MOTIF 303 307 WSXWS motif.
FT SITE 245 245 Not glycosylated.
FT CARBOHYD 55 55 N-linked (GlcNAc...).
FT CARBOHYD 93 93 N-linked (GlcNAc...).
FT CARBOHYD 221 221 N-linked (GlcNAc...).
FT DISULFID 25 193
FT DISULFID 47 96
FT DISULFID 121 132
FT DISULFID 165 176
FT VAR_SEQ 356 365 VQDSSSVPLP -> GSRRRGSCGL (in isoform 2).
FT /FTId=VSP_001682.
FT VAR_SEQ 366 468 Missing (in isoform 2).
FT /FTId=VSP_001683.
FT VARIANT 358 358 D -> A (significantly associated with
FT circulating levels of IL6 and soluble
FT IL6R; dbSNP:rs2228145).
FT /FTId=VAR_021995.
FT VARIANT 385 385 V -> I (in dbSNP:rs28730736).
FT /FTId=VAR_049166.
FT MUTAGEN 121 121 C->S: Complete loss of ligand-binding.
FT MUTAGEN 122 122 F->A: No change of ligand-binding and IL6
FT signaling.
FT MUTAGEN 132 132 C->A: Complete loss of ligand-binding.
FT MUTAGEN 134 134 W->L: Complete loss of ligand-binding.
FT MUTAGEN 140 140 P->G: No change of ligand-binding and IL6
FT signaling.
FT MUTAGEN 153 153 F->L: No change of ligand-binding and IL6
FT signaling.
FT MUTAGEN 165 165 C->L: Complete loss of ligand-binding.
FT MUTAGEN 174 174 F->L: No change of ligand-binding and IL6
FT signaling.
FT MUTAGEN 176 176 C->A: Complete loss of ligand-binding.
FT MUTAGEN 184 184 D->T: 30% decrease of ligand-binding and
FT IL6 signaling.
FT MUTAGEN 190 190 V->G: 80% decrease of ligand-binding and
FT no IL6 signaling.
FT MUTAGEN 193 193 C->D: Complete loss of ligand-binding.
FT MUTAGEN 211 211 C->A: No change of ligand-binding and IL6
FT signaling.
FT MUTAGEN 217 217 D->V: Complete loss of ligand-binding.
FT MUTAGEN 232 232 R->S: 30% decrease of ligand-binding and
FT IL6 signaling.
FT MUTAGEN 233 233 W->Q: 30% decrease of ligand-binding and
FT increase of IL6 signaling.
FT MUTAGEN 254 254 E->A: 50% decrease of ligand-binding and
FT IL6 signaling.
FT MUTAGEN 277 277 C->D: 30% increase of ligand-binding and
FT 100% increase in IL6 signaling.
FT MUTAGEN 278 278 V->N: 50% Decrease of ligand-binding and
FT 50% increase in IL6 signaling.
FT MUTAGEN 279 279 I->D: Complete loss of ligand-binding.
FT MUTAGEN 280 280 H->I: No change of ligand-binding and no
FT IL6 signaling.
FT MUTAGEN 281 281 D->G: 70% decrease of ligand-binding and
FT no IL6 signaling.
FT MUTAGEN 285 285 G->D: 80% decrease of ligand-binding and
FT no IL6 signaling.
FT MUTAGEN 291 291 Q->K: Complete loss of ligand-binding.
FT MUTAGEN 293 293 R->G: Complete loss of ligand-binding.
FT CONFLICT 210 210 G -> D (in Ref. 5; BAD97302).
FT STRAND 34 37
FT STRAND 43 46
FT STRAND 56 63
FT STRAND 65 68
FT STRAND 72 83
FT HELIX 88 90
FT STRAND 92 101
FT STRAND 105 110
FT STRAND 120 125
FT STRAND 130 134
FT STRAND 145 157
FT STRAND 159 168
FT TURN 169 172
FT STRAND 173 178
FT STRAND 187 196
FT STRAND 199 202
FT STRAND 206 209
FT TURN 210 212
FT STRAND 220 226
FT STRAND 234 239
FT STRAND 247 249
FT STRAND 251 259
FT STRAND 266 269
FT HELIX 271 273
FT STRAND 275 281
FT STRAND 288 296
FT TURN 297 299
FT STRAND 310 312
SQ SEQUENCE 468 AA; 51548 MW; 62AA239FA14F1B8B CRC64;
MLAVGCALLA ALLAAPGAAL APRRCPAQEV ARGVLTSLPG DSVTLTCPGV EPEDNATVHW
VLRKPAAGSH PSRWAGMGRR LLLRSVQLHD SGNYSCYRAG RPAGTVHLLV DVPPEEPQLS
CFRKSPLSNV VCEWGPRSTP SLTTKAVLLV RKFQNSPAED FQEPCQYSQE SQKFSCQLAV
PEGDSSFYIV SMCVASSVGS KFSKTQTFQG CGILQPDPPA NITVTAVARN PRWLSVTWQD
PHSWNSSFYR LRFELRYRAE RSKTFTTWMV KDLQHHCVIH DAWSGLRHVV QLRAQEEFGQ
GEWSEWSPEA MGTPWTESRS PPAENEVSTP MQALTTNKDD DNILFRDSAN ATSLPVQDSS
SVPLPTFLVA GGSLAFGTLL CIAIVLRFKK TWKLRALKEG KTSMHPPYSL GQLVPERPRP
TPVLVPLISP PVSPSSLGSD NTSSHNRPDA RDPRSPYDIS NTDYFFPR
//
MIM
147880
*RECORD*
*FIELD* NO
147880
*FIELD* TI
*147880 INTERLEUKIN 6 RECEPTOR; IL6R
;;INTERLEUKIN 6 RECEPTOR, ALPHA; IL6RA;;
CD126
read more*FIELD* TX
CLONING
Interleukin-6 (IL6; 147620) is a multifunctional cytokine that is
essential to the regulation of the immune response, hematopoiesis, and
acute-phase reactions. It exerts its many actions through a
heterodimeric receptor consisting of 2 membrane-bound glycoproteins: an
80-kD IL6-binding subunit, IL6R-alpha, and gp130 (IL6ST; 600694), which
is responsible for signal transduction and stabilization of the
alpha-chain ligand complex. Yamasaki et al. (1988) isolated a cDNA
encoding the receptor for interleukin-6. They showed that it codes for a
protein consisting of 468 amino acids, including a signal peptide of
about 19 amino acids and a domain of about 90 amino acids that is
similar to a domain in the immunoglobulin superfamily. The cytoplasmic
domain of about 82 amino acids lacks a tyrosine/kinase domain, unlike
other growth factor receptors.
GENE STRUCTURE
Wang et al. (2005) determined that the IL6RA gene comprises 10 exons.
MAPPING
Szpirer et al. (1991) assigned the IL6R gene to human chromosome 1 and
rat chromosome 2 by Southern analysis of 2 panels of somatic cell
hybrids segregating either human or rat chromosomes. An IL6R-like
(IL6RL) locus was also assigned to human chromosome 9. By means of
fluorescence in situ hybridization, Kluck et al. (1993) mapped the IL6RA
gene to 1q21.
BIOCHEMICAL FEATURES
Because circulating levels of IL6 and IL6R are reportedly elevated in
patients with hyperparathyroidism (see HRPT1; 145000), Nakchbandi et al.
(2002) studied whether measures of this cytokine axis could be helpful
in determining the risk for bone loss in hyperparathyroidism. They
prospectively followed 23 patients with hyperparathyroidism and found
that baseline circulating levels of IL6R correlated significantly with
rates of bone loss at the total femur (r = -0.53, P less than 0.01).
Furthermore, the combination of a serum IL6R in the upper tertile and
IL6 in the upper half of values in the whole group defined a subset of
patients with a significantly greater rate of yearly bone loss at the
total femur than the remainder of the group (P less than 0.05). They
concluded that the combined measurements of serum IL6R and IL6 may be
helpful in identifying patients with untreated hyperparathyroidism who
are more likely to experience bone loss at the total femur.
- Crystal Structure
IL6 is an immunoregulatory cytokine that activates a cell-surface
signaling assembly composed of IL6, IL6RA, and the shared signaling
receptor gp130. Boulanger et al. (2003) solved the crystal structure of
the extracellular signaling complex to 3.65-angstrom resolution, which
revealed a hexameric, interlocking assembly mediated by a total of 10
symmetry-related, thermodynamically coupled interfaces. Assembly of the
hexameric complex occurs sequentially: IL6 is first engaged by
IL6R-alpha and then presented to gp130 in the proper geometry to
facilitate a cooperative transition into the high affinity,
signaling-competent hexamer. The quaternary structures of other IL6/IL12
family signaling complexes are likely constructed by means of a similar
topologic blueprint.
GENE FUNCTION
By coimmunoprecipitation analysis using 2 differently tagged human IL6R
variants expressed in COS-7 cells, Schuster et al. (2003) showed that an
IL6R dimer existed in the plasma membrane in the absence of IL6. Ligand
binding did not appear to affect IL6R dimerization status. When COS-7
cell lysates expressing only 1 of the IL6R variants were mixed,
spontaneous dimerization occurred. Schuster et al. (2003) concluded that
IL6R dimerization occurs both on the cell surface and in solution.
MOLECULAR GENETICS
Wang et al. (2005) screened the IL6R gene for variation associated with
type 2 diabetes (125853) in Northern European Caucasian and African
American ethnic groups. They identified 11 variants with a minor allele
frequency over 5%, including 2 amino acid changes and 4 variants in the
3-prime untranslated region. No variant was associated with obesity or
measures of insulin sensitivity, but 2 single-nucleotide polymorphisms
(SNPs) in the 3-prime untranslated region showed a trend to an
association with type 2 diabetes in all Caucasians, and 3 SNPs showed a
trend to an association with type 2 diabetes among the subset of
Northern European Caucasians. Variant V385I was unique to African
Americans and was significantly associated with diabetes and diabetic
nephropathy. The authors concluded that IL6R is not likely to explain
the linkage to diabetes in the 1q21 region (Elbein et al., 1999), but
that their results support a minor role of variants in type 2 diabetes
risk and suggest that sequence variants may alter IL6R mRNA levels and
possibly levels of soluble IL6R (IL6SR). IL6SR is formed by cleavage of
IL6R from the cell membrane (Galicia et al., 2004).
Circulating levels of inflammatory markers can predict cardiovascular
disease risk. To identify genes influencing the levels of these markers,
Reich et al. (2007) genotyped 1,343 SNPs in 1,184 African Americans from
the Health, Aging and Body Composition (Health ABC) Study. Using
admixture mapping, they found a significant association of IL6SR (see
614689) with European ancestry on chromosome 1 (lod 4.59), in a region
(1q21.3) that includes the IL6R gene. Genotyping 19 SNPs showed that the
effect was largely explained by an allele of a nonsynonymous SNP in
IL6R, dbSNP rs8192284 (147880.0001), at 4% frequency in West Africans
and at 35% frequency in European Americans, first described as
associated with IL6SR in a Japanese cohort (Galicia et al., 2004). Reich
et al. (2007) replicated this association (P much less than 1.0 x
10(-12)) and also demonstrated a new association with circulating levels
of a different molecule, IL6 (P less than 3.4 x 10(-5)) (see 614752).
After replication in 1,674 European Americans from Health ABC, the
combined result was even more significant: P much less than 1.0 x
10(-12) for IL6SR, and P less than 2.0 x 10(-9) for IL6. After
correction for covariates, there was a 1.09- to 1.13-fold increase in
IL6SR levels with 1 copy of the C allele of dbSNP rs8192284 and a 1.24-
to 1.43-fold increase with 2 copies, and there was a 1.06- to 1.15-fold
increase in IL6 levels with 1 copy of the C allele and a 1.22- to
1.43-fold increase with 2 copies. Surveying cell lines from several
different ethnic groups showed no evidence of an association of surface
IL6R with dbSNP rs8192284. This finding supported the hypothesis of
Galicia et al. (2004) that the mechanism of action of dbSNP rs8192284 is
to affect cleavage efficiency, because the SNP occurs at the proteolytic
cleavage site of IL6R.
ANIMAL MODEL
Doganci et al. (2005) observed that patients with allergic asthma had
increased levels of soluble IL6R (sIL6R) in their airways compared with
controls. Blockade of sIl6r in a murine model of late-phase asthma led
to suppression of Th2 cells in lungs. In contrast, blockade of
membrane-bound Il6r (mIl6r) induced local expansion of Foxp3
(300292)-positive/Cd4 (186940)-positive/Cd25 (IL2RA; 147730)-positive
regulatory T cells with increased immunosuppressive capacities. These
cells, but not Cd4-positive/Cd25-negative cells, expressed Il6ra and
showed Il6-dependent Stat3 (102582) phosphorylation. Cells from
anti-Il6r antibody-treated mice adoptively transferred to Rag1
(179615)-deficient mice showed marked immunosuppressive and
antiinflammatory functions. Doganci et al. (2005) concluded that IL6
signaling controls the balance between effector cells and regulatory T
cells in lungs, with sIL6R regulating Th2 cell functions in
CD4-positive/CD25-negative T-effector cells lacking mIL6R, and mIL6R
controlling cell fate at the beginning of T-cell differentiation by
directing CD4-positive naive cells toward Th2 pathways and inhibiting
regulatory T-cell differentiation. They suggested that blockade of IL6
signaling may be a useful approach in the treatment of Th2-dependent
inflammatory processes, such as allergic asthma.
McFarland-Mancini et al. (2010) noted that IL6 is essential for timely
wound healing. Unexpectedly, they found that Il6r-alpha-deficient mice
showed no delay in wound healing, although they shared many inflammatory
deficits with Il6-deficient mice. Mice lacking both Il6 and Il6r-alpha,
or mice lacking Il6 and treated with antibody to Il6r-alpha, exhibited
improved wound healing, in terms of macrophage infiltration, fibrin
clearance, and wound contraction, compared with Il6-deficient mice.
Il6r-alpha-deficient mice appeared to have aberrant MAP kinase
activation, which may have contributed to improved healing.
*FIELD* AV
.0001
SOLUBLE INTERLEUKIN-6 RECEPTOR, SERUM LEVEL OF, QUANTITATIVE TRAIT
LOCUS
INTERLEUKIN 6, SERUM LEVEL OF, QUANTITATIVE TRAIT LOCUS, INCLUDED
IL6R, ASP358ALA (dbSNP rs8192284)
In a study using admixture mapping to locate regions of the genome
associated with acute-phase inflammatory markers and soluble receptors,
Reich et al. (2007) identified a missense SNP, dbSNP rs8192284, that was
significantly associated with circulating levels of IL6SR (614689). This
SNP, an A-to-C transversion that results in an asp358-to-ala (D358A)
amino acid substitution, is present in approximately 35% of Europeans
and 4% of West Africans and accounted for the admixture peak within a
40-kb segment on chromosome 1q21.3. Galicia et al. (2004), who had
identified the association of dbSNP rs8192284 with IL6SR in Japanese,
noted that this SNP occurs at the proteolytic cleavage site of IL6R and
that consequently, variability could affect the level of the circulating
soluble receptor. Reich et al. (2007) also identified an association
between this SNP and IL6 (147620) levels (614752) in both European
Americans and African Americans. After correction for covariates, there
was a 1.09- to 1.13-fold increase in IL6SR levels with 1 copy of the C
allele of dbSNP rs8192284 and a 1.24- to 1.43-fold increase with 2
copies, and there was a 1.06- to 1.15-fold increase in IL6 levels with 1
copy of the C allele and a 1.22- to 1.43-fold increase with 2 copies.
Surveying cell lines from several different ethnic groups showed no
evidence of an association of surface IL6R with dbSNP rs8192284,
supporting the hypothesis of Galicia et al. (2004) that the mechanism of
action of dbSNP rs8192284 is to affect cleavage efficiency.
*FIELD* RF
1. Boulanger, M. J.; Chow, D.; Brevnova, E. E.; Garcia, K. C.: Hexameric
structure and assembly of the interleukin-6/IL-6 alpha-receptor/gp130
complex. Science 300: 2101-2104, 2003. Note: Erratum: Science 301:
918 only, 2003.
2. Doganci, A.; Eigenbrod, T.; Krug, N.; De Sanctis, G. T.; Hausding,
M.; Erpenbeck, V. J.; Haddad, E.-B.; Lehr, H. A.; Schmitt, E.; Bopp,
T.; Kallen, K.-J.; Herz, U.; and 13 others: The IL-6R alpha chain
controls lung CD4+CD25+ Treg development and function during allergic
airway inflammation in vivo. J. Clin. Invest. 115: 313-325, 2005.
Note: Erratum: J. Clin. Invest. 115: 1388 only, 2005.
3. Elbein, S. C.; Hoffman, M. D.; Teng, K.; Leppert, M. F.; Hasstedt,
S. J.: A genome-wide search for type 2 diabetes susceptibility genes
in Utah Caucasians. Diabetes 48: 1175-1182, 1999.
4. Galicia, J. C.; Tai, H.; Komatsu, Y.; Shimada, Y.; Akazawa, K.;
Yoshie, H.: Polymorphisms in the IL-6 receptor (IL-6R) gene: strong
evidence that serum levels of soluble IL-6R are genetically influenced. Genes
Immun. 5: 513-516, 2004.
5. Kluck, P. M. C.; Wiegant, J.; Jansen, R. P. M.; Bolk, M. W. J.;
Raap, A. K.; Willemze, R.; Landegent, J. E.: The human interleukin-6
receptor alpha-chain gene is localized on chromosome 1 band q21. Hum.
Genet. 90: 542-544, 1993.
6. McFarland-Mancini, M. M.; Funk, H. M.; Paluch, A. M.; Zhou, M.;
Giridhar, P. V.; Mercer, C. A.; Kozma, S. C.; Drew, A. F.: Differences
in wound healing in mice with deficiency of IL-6 versus IL-6 receptor. J.
Immun. 184: 7219-7228, 2010.
7. Nakchbandi, I. A.; Mitnick, M. A.; Lang, R.; Gundberg, C.; Kinder,
B.; Insogna, K.: Circulating levels of interleukin-6 soluble receptor
predict rates of bone loss in patients with primary hyperparathyroidism. J.
Clin. Endocr. Metab. 87: 4946-4951, 2002.
8. Reich, D.; Patterson, N.; Ramesh, V.; De Jager, P. L.; McDonald,
G. J.; Tandon, A.; Choy, E.; Hu, D.; Tamraz, B.; Pawlikowska, L.;
Wassel-Fyr, C.; Huntsman, S.; and 11 others: Admixture mapping
of an allele affecting interleukin 6 soluble receptor and interleukin
6 levels. Am. J. Hum. Genet. 80: 716-726, 2007.
9. Schuster, B.; Meinert, W.; Rose-John, S.; Kallen, K.-J.: The human
interleukin-6 (IL-6) receptor exists as a preformed dimer in the plasma
membrane. FEBS Lett. 538: 113-116, 2003.
10. Szpirer, J.; Szpirer, C.; Riviere, M.; Houart, C.; Baumann, M.;
Fey, G. H.; Poli, V.; Cortese, R.; Islam, M. Q.; Levan, G.: The interleukin-6-dependent
DNA-binding protein gene (transcription factor 5: TCF5) maps to human
chromosome 20 and rat chromosome 3, the IL6 receptor locus (IL6R)
to human chromosome 1 and rat chromosome 2, and the rat IL6 gene to
rat chromosome 4. Genomics 10: 539-546, 1991.
11. Wang, H.; Zhang, Z.; Chu, W.; Hale, T.; Cooper, J. J.; Elbein,
S. C.: Molecular screening and association analyses of the interleukin
6 receptor gene variants with type 2 diabetes, diabetic nephropathy,
and insulin sensitivity. J. Clin. Endocr. Metab. 90: 1123-1129,
2005.
12. Yamasaki, K.; Taga, T.; Hirata, Y.; Yawata, H.; Kawanishi, Y.;
Seed, B.; Taniguchi, T.; Hirano, T.; Kishimoto, T.: Cloning and expression
of the human interleukin-6 (BSF-2/IFN-beta-2) receptor. Science 241:
825-828, 1988.
*FIELD* CN
Paul J. Converse - updated: 11/19/2012
Paul J. Converse - updated: 8/1/2012
Matthew B. Gross - updated: 7/25/2008
Victor A. McKusick - updated: 3/27/2007
John A. Phillips, III - updated: 8/22/2006
Paul J. Converse - updated: 4/18/2005
Ada Hamosh - updated: 7/8/2003
John A. Phillips, III - updated: 4/8/2003
*FIELD* CD
Victor A. McKusick: 9/15/1988
*FIELD* ED
mgross: 11/26/2012
terry: 11/19/2012
terry: 8/6/2012
mgross: 8/3/2012
terry: 8/3/2012
mgross: 8/1/2012
mgross: 6/20/2012
wwang: 11/5/2008
wwang: 7/28/2008
mgross: 7/25/2008
terry: 9/20/2007
alopez: 6/6/2007
alopez: 4/3/2007
terry: 3/27/2007
alopez: 8/22/2006
wwang: 5/24/2005
mgross: 4/18/2005
alopez: 7/10/2003
terry: 7/8/2003
cwells: 4/29/2003
terry: 4/8/2003
carol: 1/29/1999
dkim: 7/23/1998
terry: 3/26/1998
terry: 7/28/1995
carol: 4/2/1993
supermim: 3/16/1992
carol: 6/21/1991
carol: 3/7/1991
carol: 3/6/1991
*RECORD*
*FIELD* NO
147880
*FIELD* TI
*147880 INTERLEUKIN 6 RECEPTOR; IL6R
;;INTERLEUKIN 6 RECEPTOR, ALPHA; IL6RA;;
CD126
read more*FIELD* TX
CLONING
Interleukin-6 (IL6; 147620) is a multifunctional cytokine that is
essential to the regulation of the immune response, hematopoiesis, and
acute-phase reactions. It exerts its many actions through a
heterodimeric receptor consisting of 2 membrane-bound glycoproteins: an
80-kD IL6-binding subunit, IL6R-alpha, and gp130 (IL6ST; 600694), which
is responsible for signal transduction and stabilization of the
alpha-chain ligand complex. Yamasaki et al. (1988) isolated a cDNA
encoding the receptor for interleukin-6. They showed that it codes for a
protein consisting of 468 amino acids, including a signal peptide of
about 19 amino acids and a domain of about 90 amino acids that is
similar to a domain in the immunoglobulin superfamily. The cytoplasmic
domain of about 82 amino acids lacks a tyrosine/kinase domain, unlike
other growth factor receptors.
GENE STRUCTURE
Wang et al. (2005) determined that the IL6RA gene comprises 10 exons.
MAPPING
Szpirer et al. (1991) assigned the IL6R gene to human chromosome 1 and
rat chromosome 2 by Southern analysis of 2 panels of somatic cell
hybrids segregating either human or rat chromosomes. An IL6R-like
(IL6RL) locus was also assigned to human chromosome 9. By means of
fluorescence in situ hybridization, Kluck et al. (1993) mapped the IL6RA
gene to 1q21.
BIOCHEMICAL FEATURES
Because circulating levels of IL6 and IL6R are reportedly elevated in
patients with hyperparathyroidism (see HRPT1; 145000), Nakchbandi et al.
(2002) studied whether measures of this cytokine axis could be helpful
in determining the risk for bone loss in hyperparathyroidism. They
prospectively followed 23 patients with hyperparathyroidism and found
that baseline circulating levels of IL6R correlated significantly with
rates of bone loss at the total femur (r = -0.53, P less than 0.01).
Furthermore, the combination of a serum IL6R in the upper tertile and
IL6 in the upper half of values in the whole group defined a subset of
patients with a significantly greater rate of yearly bone loss at the
total femur than the remainder of the group (P less than 0.05). They
concluded that the combined measurements of serum IL6R and IL6 may be
helpful in identifying patients with untreated hyperparathyroidism who
are more likely to experience bone loss at the total femur.
- Crystal Structure
IL6 is an immunoregulatory cytokine that activates a cell-surface
signaling assembly composed of IL6, IL6RA, and the shared signaling
receptor gp130. Boulanger et al. (2003) solved the crystal structure of
the extracellular signaling complex to 3.65-angstrom resolution, which
revealed a hexameric, interlocking assembly mediated by a total of 10
symmetry-related, thermodynamically coupled interfaces. Assembly of the
hexameric complex occurs sequentially: IL6 is first engaged by
IL6R-alpha and then presented to gp130 in the proper geometry to
facilitate a cooperative transition into the high affinity,
signaling-competent hexamer. The quaternary structures of other IL6/IL12
family signaling complexes are likely constructed by means of a similar
topologic blueprint.
GENE FUNCTION
By coimmunoprecipitation analysis using 2 differently tagged human IL6R
variants expressed in COS-7 cells, Schuster et al. (2003) showed that an
IL6R dimer existed in the plasma membrane in the absence of IL6. Ligand
binding did not appear to affect IL6R dimerization status. When COS-7
cell lysates expressing only 1 of the IL6R variants were mixed,
spontaneous dimerization occurred. Schuster et al. (2003) concluded that
IL6R dimerization occurs both on the cell surface and in solution.
MOLECULAR GENETICS
Wang et al. (2005) screened the IL6R gene for variation associated with
type 2 diabetes (125853) in Northern European Caucasian and African
American ethnic groups. They identified 11 variants with a minor allele
frequency over 5%, including 2 amino acid changes and 4 variants in the
3-prime untranslated region. No variant was associated with obesity or
measures of insulin sensitivity, but 2 single-nucleotide polymorphisms
(SNPs) in the 3-prime untranslated region showed a trend to an
association with type 2 diabetes in all Caucasians, and 3 SNPs showed a
trend to an association with type 2 diabetes among the subset of
Northern European Caucasians. Variant V385I was unique to African
Americans and was significantly associated with diabetes and diabetic
nephropathy. The authors concluded that IL6R is not likely to explain
the linkage to diabetes in the 1q21 region (Elbein et al., 1999), but
that their results support a minor role of variants in type 2 diabetes
risk and suggest that sequence variants may alter IL6R mRNA levels and
possibly levels of soluble IL6R (IL6SR). IL6SR is formed by cleavage of
IL6R from the cell membrane (Galicia et al., 2004).
Circulating levels of inflammatory markers can predict cardiovascular
disease risk. To identify genes influencing the levels of these markers,
Reich et al. (2007) genotyped 1,343 SNPs in 1,184 African Americans from
the Health, Aging and Body Composition (Health ABC) Study. Using
admixture mapping, they found a significant association of IL6SR (see
614689) with European ancestry on chromosome 1 (lod 4.59), in a region
(1q21.3) that includes the IL6R gene. Genotyping 19 SNPs showed that the
effect was largely explained by an allele of a nonsynonymous SNP in
IL6R, dbSNP rs8192284 (147880.0001), at 4% frequency in West Africans
and at 35% frequency in European Americans, first described as
associated with IL6SR in a Japanese cohort (Galicia et al., 2004). Reich
et al. (2007) replicated this association (P much less than 1.0 x
10(-12)) and also demonstrated a new association with circulating levels
of a different molecule, IL6 (P less than 3.4 x 10(-5)) (see 614752).
After replication in 1,674 European Americans from Health ABC, the
combined result was even more significant: P much less than 1.0 x
10(-12) for IL6SR, and P less than 2.0 x 10(-9) for IL6. After
correction for covariates, there was a 1.09- to 1.13-fold increase in
IL6SR levels with 1 copy of the C allele of dbSNP rs8192284 and a 1.24-
to 1.43-fold increase with 2 copies, and there was a 1.06- to 1.15-fold
increase in IL6 levels with 1 copy of the C allele and a 1.22- to
1.43-fold increase with 2 copies. Surveying cell lines from several
different ethnic groups showed no evidence of an association of surface
IL6R with dbSNP rs8192284. This finding supported the hypothesis of
Galicia et al. (2004) that the mechanism of action of dbSNP rs8192284 is
to affect cleavage efficiency, because the SNP occurs at the proteolytic
cleavage site of IL6R.
ANIMAL MODEL
Doganci et al. (2005) observed that patients with allergic asthma had
increased levels of soluble IL6R (sIL6R) in their airways compared with
controls. Blockade of sIl6r in a murine model of late-phase asthma led
to suppression of Th2 cells in lungs. In contrast, blockade of
membrane-bound Il6r (mIl6r) induced local expansion of Foxp3
(300292)-positive/Cd4 (186940)-positive/Cd25 (IL2RA; 147730)-positive
regulatory T cells with increased immunosuppressive capacities. These
cells, but not Cd4-positive/Cd25-negative cells, expressed Il6ra and
showed Il6-dependent Stat3 (102582) phosphorylation. Cells from
anti-Il6r antibody-treated mice adoptively transferred to Rag1
(179615)-deficient mice showed marked immunosuppressive and
antiinflammatory functions. Doganci et al. (2005) concluded that IL6
signaling controls the balance between effector cells and regulatory T
cells in lungs, with sIL6R regulating Th2 cell functions in
CD4-positive/CD25-negative T-effector cells lacking mIL6R, and mIL6R
controlling cell fate at the beginning of T-cell differentiation by
directing CD4-positive naive cells toward Th2 pathways and inhibiting
regulatory T-cell differentiation. They suggested that blockade of IL6
signaling may be a useful approach in the treatment of Th2-dependent
inflammatory processes, such as allergic asthma.
McFarland-Mancini et al. (2010) noted that IL6 is essential for timely
wound healing. Unexpectedly, they found that Il6r-alpha-deficient mice
showed no delay in wound healing, although they shared many inflammatory
deficits with Il6-deficient mice. Mice lacking both Il6 and Il6r-alpha,
or mice lacking Il6 and treated with antibody to Il6r-alpha, exhibited
improved wound healing, in terms of macrophage infiltration, fibrin
clearance, and wound contraction, compared with Il6-deficient mice.
Il6r-alpha-deficient mice appeared to have aberrant MAP kinase
activation, which may have contributed to improved healing.
*FIELD* AV
.0001
SOLUBLE INTERLEUKIN-6 RECEPTOR, SERUM LEVEL OF, QUANTITATIVE TRAIT
LOCUS
INTERLEUKIN 6, SERUM LEVEL OF, QUANTITATIVE TRAIT LOCUS, INCLUDED
IL6R, ASP358ALA (dbSNP rs8192284)
In a study using admixture mapping to locate regions of the genome
associated with acute-phase inflammatory markers and soluble receptors,
Reich et al. (2007) identified a missense SNP, dbSNP rs8192284, that was
significantly associated with circulating levels of IL6SR (614689). This
SNP, an A-to-C transversion that results in an asp358-to-ala (D358A)
amino acid substitution, is present in approximately 35% of Europeans
and 4% of West Africans and accounted for the admixture peak within a
40-kb segment on chromosome 1q21.3. Galicia et al. (2004), who had
identified the association of dbSNP rs8192284 with IL6SR in Japanese,
noted that this SNP occurs at the proteolytic cleavage site of IL6R and
that consequently, variability could affect the level of the circulating
soluble receptor. Reich et al. (2007) also identified an association
between this SNP and IL6 (147620) levels (614752) in both European
Americans and African Americans. After correction for covariates, there
was a 1.09- to 1.13-fold increase in IL6SR levels with 1 copy of the C
allele of dbSNP rs8192284 and a 1.24- to 1.43-fold increase with 2
copies, and there was a 1.06- to 1.15-fold increase in IL6 levels with 1
copy of the C allele and a 1.22- to 1.43-fold increase with 2 copies.
Surveying cell lines from several different ethnic groups showed no
evidence of an association of surface IL6R with dbSNP rs8192284,
supporting the hypothesis of Galicia et al. (2004) that the mechanism of
action of dbSNP rs8192284 is to affect cleavage efficiency.
*FIELD* RF
1. Boulanger, M. J.; Chow, D.; Brevnova, E. E.; Garcia, K. C.: Hexameric
structure and assembly of the interleukin-6/IL-6 alpha-receptor/gp130
complex. Science 300: 2101-2104, 2003. Note: Erratum: Science 301:
918 only, 2003.
2. Doganci, A.; Eigenbrod, T.; Krug, N.; De Sanctis, G. T.; Hausding,
M.; Erpenbeck, V. J.; Haddad, E.-B.; Lehr, H. A.; Schmitt, E.; Bopp,
T.; Kallen, K.-J.; Herz, U.; and 13 others: The IL-6R alpha chain
controls lung CD4+CD25+ Treg development and function during allergic
airway inflammation in vivo. J. Clin. Invest. 115: 313-325, 2005.
Note: Erratum: J. Clin. Invest. 115: 1388 only, 2005.
3. Elbein, S. C.; Hoffman, M. D.; Teng, K.; Leppert, M. F.; Hasstedt,
S. J.: A genome-wide search for type 2 diabetes susceptibility genes
in Utah Caucasians. Diabetes 48: 1175-1182, 1999.
4. Galicia, J. C.; Tai, H.; Komatsu, Y.; Shimada, Y.; Akazawa, K.;
Yoshie, H.: Polymorphisms in the IL-6 receptor (IL-6R) gene: strong
evidence that serum levels of soluble IL-6R are genetically influenced. Genes
Immun. 5: 513-516, 2004.
5. Kluck, P. M. C.; Wiegant, J.; Jansen, R. P. M.; Bolk, M. W. J.;
Raap, A. K.; Willemze, R.; Landegent, J. E.: The human interleukin-6
receptor alpha-chain gene is localized on chromosome 1 band q21. Hum.
Genet. 90: 542-544, 1993.
6. McFarland-Mancini, M. M.; Funk, H. M.; Paluch, A. M.; Zhou, M.;
Giridhar, P. V.; Mercer, C. A.; Kozma, S. C.; Drew, A. F.: Differences
in wound healing in mice with deficiency of IL-6 versus IL-6 receptor. J.
Immun. 184: 7219-7228, 2010.
7. Nakchbandi, I. A.; Mitnick, M. A.; Lang, R.; Gundberg, C.; Kinder,
B.; Insogna, K.: Circulating levels of interleukin-6 soluble receptor
predict rates of bone loss in patients with primary hyperparathyroidism. J.
Clin. Endocr. Metab. 87: 4946-4951, 2002.
8. Reich, D.; Patterson, N.; Ramesh, V.; De Jager, P. L.; McDonald,
G. J.; Tandon, A.; Choy, E.; Hu, D.; Tamraz, B.; Pawlikowska, L.;
Wassel-Fyr, C.; Huntsman, S.; and 11 others: Admixture mapping
of an allele affecting interleukin 6 soluble receptor and interleukin
6 levels. Am. J. Hum. Genet. 80: 716-726, 2007.
9. Schuster, B.; Meinert, W.; Rose-John, S.; Kallen, K.-J.: The human
interleukin-6 (IL-6) receptor exists as a preformed dimer in the plasma
membrane. FEBS Lett. 538: 113-116, 2003.
10. Szpirer, J.; Szpirer, C.; Riviere, M.; Houart, C.; Baumann, M.;
Fey, G. H.; Poli, V.; Cortese, R.; Islam, M. Q.; Levan, G.: The interleukin-6-dependent
DNA-binding protein gene (transcription factor 5: TCF5) maps to human
chromosome 20 and rat chromosome 3, the IL6 receptor locus (IL6R)
to human chromosome 1 and rat chromosome 2, and the rat IL6 gene to
rat chromosome 4. Genomics 10: 539-546, 1991.
11. Wang, H.; Zhang, Z.; Chu, W.; Hale, T.; Cooper, J. J.; Elbein,
S. C.: Molecular screening and association analyses of the interleukin
6 receptor gene variants with type 2 diabetes, diabetic nephropathy,
and insulin sensitivity. J. Clin. Endocr. Metab. 90: 1123-1129,
2005.
12. Yamasaki, K.; Taga, T.; Hirata, Y.; Yawata, H.; Kawanishi, Y.;
Seed, B.; Taniguchi, T.; Hirano, T.; Kishimoto, T.: Cloning and expression
of the human interleukin-6 (BSF-2/IFN-beta-2) receptor. Science 241:
825-828, 1988.
*FIELD* CN
Paul J. Converse - updated: 11/19/2012
Paul J. Converse - updated: 8/1/2012
Matthew B. Gross - updated: 7/25/2008
Victor A. McKusick - updated: 3/27/2007
John A. Phillips, III - updated: 8/22/2006
Paul J. Converse - updated: 4/18/2005
Ada Hamosh - updated: 7/8/2003
John A. Phillips, III - updated: 4/8/2003
*FIELD* CD
Victor A. McKusick: 9/15/1988
*FIELD* ED
mgross: 11/26/2012
terry: 11/19/2012
terry: 8/6/2012
mgross: 8/3/2012
terry: 8/3/2012
mgross: 8/1/2012
mgross: 6/20/2012
wwang: 11/5/2008
wwang: 7/28/2008
mgross: 7/25/2008
terry: 9/20/2007
alopez: 6/6/2007
alopez: 4/3/2007
terry: 3/27/2007
alopez: 8/22/2006
wwang: 5/24/2005
mgross: 4/18/2005
alopez: 7/10/2003
terry: 7/8/2003
cwells: 4/29/2003
terry: 4/8/2003
carol: 1/29/1999
dkim: 7/23/1998
terry: 3/26/1998
terry: 7/28/1995
carol: 4/2/1993
supermim: 3/16/1992
carol: 6/21/1991
carol: 3/7/1991
carol: 3/6/1991
MIM
614689
*RECORD*
*FIELD* NO
614689
*FIELD* TI
#614689 SOLUBLE INTERLEUKIN-6 RECEPTOR, SERUM LEVEL OF, QUANTITATIVE TRAIT
LOCUS
;;SOLUBLE IL6R, SERUM LEVEL OF, QUANTITATIVE TRAIT LOCUS
read more*FIELD* TX
A number sign (#) is used with this entry because the serum level of
interleukin-6 soluble receptor (IL6R; 147880) is associated with a
polymorphism in the IL6R gene (147880) on chromosome 1q21.3.
MAPPING
Circulating levels of inflammatory markers can predict cardiovascular
disease risk. To identify genes influencing the levels of these markers,
Reich et al. (2007) genotyped 1,343 SNPs in 1,184 African Americans from
the Health, Aging and Body Composition (Health ABC) Study. Using
admixture mapping, they found a significant association of interleukin-6
soluble receptor (IL6SR) with European ancestry on chromosome 1 (lod
4.59), in a region (1q21.3) that includes the IL6R gene. Genotyping 19
SNPs showed that the effect was largely explained by an allele of a
nonsynonymous SNP in IL6R, dbSNP rs8192284 (147880.0001), at 4%
frequency in West Africans and at 35% frequency in European Americans,
first described as associated with IL6SR in a Japanese cohort (Galicia
et al., 2004). Reich et al. (2007) replicated this association (P much
less than 1.0 x 10(-12)) and also demonstrated a new association with
circulating levels of a different molecule, interleukin-6 (IL6; 147620)
(P less than 3.4 x 10(-5)) (see 614752). After replication in 1,674
European Americans from Health ABC, the combined result was even more
significant: P much less than 1.0 x 10(-12) for IL6SR, and P less than
2.0 x 10(-9) for IL6. After correction for covariates, there was a 1.09-
to 1.13-fold increase in IL6SR levels with 1 copy of the C allele of
dbSNP rs8192284 and a 1.24- to 1.43-fold increase with 2 copies, and
there was a 1.06- to 1.15-fold increase in IL6 levels with 1 copy of the
C allele and a 1.22- to 1.43-fold increase with 2 copies. Surveying cell
lines from several different ethnic groups showed no evidence of an
association of surface IL6R with dbSNP rs8192284. This finding supported
the hypothesis of Galicia et al. (2004) that the mechanism of action of
dbSNP rs8192284 is to affect cleavage efficiency, because the SNP occurs
at the proteolytic cleavage site of IL6R.
*FIELD* RF
1. Galicia, J. C.; Tai, H.; Komatsu, Y.; Shimada, Y.; Akazawa, K.;
Yoshie, H.: Polymorphisms in the IL-6 receptor (IL-6R) gene: strong
evidence that serum levels of soluble IL-6R are genetically influenced. Genes
Immun. 5: 513-516, 2004.
2. Reich, D.; Patterson, N.; Ramesh, V.; De Jager, P. L.; McDonald,
G. J.; Tandon, A.; Choy, E.; Hu, D.; Tamraz, B.; Pawlikowska, L.;
Wassel-Fyr, C.; Huntsman, S.; and 11 others: Admixture mapping
of an allele affecting interleukin 6 soluble receptor and interleukin
6 levels. Am. J. Hum. Genet. 80: 716-726, 2007.
*FIELD* CN
Paul J. Converse - updated: 8/1/2012
*FIELD* CD
Matthew B. Gross: 6/20/2012
*FIELD* ED
mgross: 08/01/2012
mgross: 8/1/2012
mgross: 7/25/2012
mgross: 7/23/2012
mgross: 6/20/2012
*RECORD*
*FIELD* NO
614689
*FIELD* TI
#614689 SOLUBLE INTERLEUKIN-6 RECEPTOR, SERUM LEVEL OF, QUANTITATIVE TRAIT
LOCUS
;;SOLUBLE IL6R, SERUM LEVEL OF, QUANTITATIVE TRAIT LOCUS
read more*FIELD* TX
A number sign (#) is used with this entry because the serum level of
interleukin-6 soluble receptor (IL6R; 147880) is associated with a
polymorphism in the IL6R gene (147880) on chromosome 1q21.3.
MAPPING
Circulating levels of inflammatory markers can predict cardiovascular
disease risk. To identify genes influencing the levels of these markers,
Reich et al. (2007) genotyped 1,343 SNPs in 1,184 African Americans from
the Health, Aging and Body Composition (Health ABC) Study. Using
admixture mapping, they found a significant association of interleukin-6
soluble receptor (IL6SR) with European ancestry on chromosome 1 (lod
4.59), in a region (1q21.3) that includes the IL6R gene. Genotyping 19
SNPs showed that the effect was largely explained by an allele of a
nonsynonymous SNP in IL6R, dbSNP rs8192284 (147880.0001), at 4%
frequency in West Africans and at 35% frequency in European Americans,
first described as associated with IL6SR in a Japanese cohort (Galicia
et al., 2004). Reich et al. (2007) replicated this association (P much
less than 1.0 x 10(-12)) and also demonstrated a new association with
circulating levels of a different molecule, interleukin-6 (IL6; 147620)
(P less than 3.4 x 10(-5)) (see 614752). After replication in 1,674
European Americans from Health ABC, the combined result was even more
significant: P much less than 1.0 x 10(-12) for IL6SR, and P less than
2.0 x 10(-9) for IL6. After correction for covariates, there was a 1.09-
to 1.13-fold increase in IL6SR levels with 1 copy of the C allele of
dbSNP rs8192284 and a 1.24- to 1.43-fold increase with 2 copies, and
there was a 1.06- to 1.15-fold increase in IL6 levels with 1 copy of the
C allele and a 1.22- to 1.43-fold increase with 2 copies. Surveying cell
lines from several different ethnic groups showed no evidence of an
association of surface IL6R with dbSNP rs8192284. This finding supported
the hypothesis of Galicia et al. (2004) that the mechanism of action of
dbSNP rs8192284 is to affect cleavage efficiency, because the SNP occurs
at the proteolytic cleavage site of IL6R.
*FIELD* RF
1. Galicia, J. C.; Tai, H.; Komatsu, Y.; Shimada, Y.; Akazawa, K.;
Yoshie, H.: Polymorphisms in the IL-6 receptor (IL-6R) gene: strong
evidence that serum levels of soluble IL-6R are genetically influenced. Genes
Immun. 5: 513-516, 2004.
2. Reich, D.; Patterson, N.; Ramesh, V.; De Jager, P. L.; McDonald,
G. J.; Tandon, A.; Choy, E.; Hu, D.; Tamraz, B.; Pawlikowska, L.;
Wassel-Fyr, C.; Huntsman, S.; and 11 others: Admixture mapping
of an allele affecting interleukin 6 soluble receptor and interleukin
6 levels. Am. J. Hum. Genet. 80: 716-726, 2007.
*FIELD* CN
Paul J. Converse - updated: 8/1/2012
*FIELD* CD
Matthew B. Gross: 6/20/2012
*FIELD* ED
mgross: 08/01/2012
mgross: 8/1/2012
mgross: 7/25/2012
mgross: 7/23/2012
mgross: 6/20/2012
MIM
614752
*RECORD*
*FIELD* NO
614752
*FIELD* TI
#614752 INTERLEUKIN 6, SERUM LEVEL OF, QUANTITATIVE TRAIT LOCUS
;;IL6, SERUM LEVEL OF, QUANTITATIVE TRAIT LOCUS
read more*FIELD* TX
A number sign (#) is used with this entry because the serum level of
interleukin-6 (IL6; 147620) is associated with a polymorphism in the
gene encoding interleukin-6 receptor (147880) on chromosome 1q21.3.
MAPPING
Circulating levels of inflammatory markers can predict cardiovascular
disease risk. To identify genes influencing the levels of these markers,
Reich et al. (2007) genotyped 1,343 SNPs in 1,184 African Americans from
the Health, Aging and Body Composition (Health ABC) Study. Using
admixture mapping, they found a significant association of interleukin-6
soluble receptor (IL6SR; see 614689) with European ancestry on
chromosome 1 (lod 4.59), in a region (1q21.3) that includes the IL6R
gene. Genotyping 19 SNPs showed that the effect was largely explained by
an allele of a nonsynonymous SNP in IL6R, dbSNP rs8192284 (147880.0001),
at 4% frequency in West Africans and at 35% frequency in European
Americans, first described as associated with IL6SR in a Japanese cohort
(Galicia et al., 2004). Reich et al. (2007) replicated this association
(P much less than 1.0 x 10(-12)) and also demonstrated a new association
with circulating levels of a different molecule, IL6 (P less than 3.4 x
10(-5)). After replication in 1,674 European Americans from Health ABC,
the combined result was even more significant: P much less than 1.0 x
10(-12) for IL6SR, and P less than 2.0 x 10(-9) for IL6. After
correction for covariates, there was a 1.09- to 1.13-fold increase in
IL6SR levels with 1 copy of the C allele of dbSNP rs8192284 and a 1.24-
to 1.43-fold increase with 2 copies, and there was a 1.06- to 1.15-fold
increase in IL6 levels with 1 copy of the C allele and a 1.22- to
1.43-fold increase with 2 copies. Surveying cell lines from several
different ethnic groups showed no evidence of an association of surface
IL6R with dbSNP rs8192284. This finding supported the hypothesis of
Galicia et al. (2004) that the mechanism of action of dbSNP rs8192284 is
to affect cleavage efficiency, because the SNP occurs at the proteolytic
cleavage site of IL6R.
*FIELD* RF
1. Galicia, J. C.; Tai, H.; Komatsu, Y.; Shimada, Y.; Akazawa, K.;
Yoshie, H.: Polymorphisms in the IL-6 receptor (IL-6R) gene: strong
evidence that serum levels of soluble IL-6R are genetically influenced. Genes
Immun. 5: 513-516, 2004.
2. Reich, D.; Patterson, N.; Ramesh, V.; De Jager, P. L.; McDonald,
G. J.; Tandon, A.; Choy, E.; Hu, D.; Tamraz, B.; Pawlikowska, L.;
Wassel-Fyr, C.; Huntsman, S.; and 11 others: Admixture mapping
of an allele affecting interleukin 6 soluble receptor and interleukin
6 levels. Am. J. Hum. Genet. 80: 716-726, 2007.
*FIELD* CN
Paul J. Converse - updated: 8/1/2012
*FIELD* CD
Matthew B. Gross: 8/1/2012
*FIELD* ED
mgross: 08/01/2012
mgross: 8/1/2012
*RECORD*
*FIELD* NO
614752
*FIELD* TI
#614752 INTERLEUKIN 6, SERUM LEVEL OF, QUANTITATIVE TRAIT LOCUS
;;IL6, SERUM LEVEL OF, QUANTITATIVE TRAIT LOCUS
read more*FIELD* TX
A number sign (#) is used with this entry because the serum level of
interleukin-6 (IL6; 147620) is associated with a polymorphism in the
gene encoding interleukin-6 receptor (147880) on chromosome 1q21.3.
MAPPING
Circulating levels of inflammatory markers can predict cardiovascular
disease risk. To identify genes influencing the levels of these markers,
Reich et al. (2007) genotyped 1,343 SNPs in 1,184 African Americans from
the Health, Aging and Body Composition (Health ABC) Study. Using
admixture mapping, they found a significant association of interleukin-6
soluble receptor (IL6SR; see 614689) with European ancestry on
chromosome 1 (lod 4.59), in a region (1q21.3) that includes the IL6R
gene. Genotyping 19 SNPs showed that the effect was largely explained by
an allele of a nonsynonymous SNP in IL6R, dbSNP rs8192284 (147880.0001),
at 4% frequency in West Africans and at 35% frequency in European
Americans, first described as associated with IL6SR in a Japanese cohort
(Galicia et al., 2004). Reich et al. (2007) replicated this association
(P much less than 1.0 x 10(-12)) and also demonstrated a new association
with circulating levels of a different molecule, IL6 (P less than 3.4 x
10(-5)). After replication in 1,674 European Americans from Health ABC,
the combined result was even more significant: P much less than 1.0 x
10(-12) for IL6SR, and P less than 2.0 x 10(-9) for IL6. After
correction for covariates, there was a 1.09- to 1.13-fold increase in
IL6SR levels with 1 copy of the C allele of dbSNP rs8192284 and a 1.24-
to 1.43-fold increase with 2 copies, and there was a 1.06- to 1.15-fold
increase in IL6 levels with 1 copy of the C allele and a 1.22- to
1.43-fold increase with 2 copies. Surveying cell lines from several
different ethnic groups showed no evidence of an association of surface
IL6R with dbSNP rs8192284. This finding supported the hypothesis of
Galicia et al. (2004) that the mechanism of action of dbSNP rs8192284 is
to affect cleavage efficiency, because the SNP occurs at the proteolytic
cleavage site of IL6R.
*FIELD* RF
1. Galicia, J. C.; Tai, H.; Komatsu, Y.; Shimada, Y.; Akazawa, K.;
Yoshie, H.: Polymorphisms in the IL-6 receptor (IL-6R) gene: strong
evidence that serum levels of soluble IL-6R are genetically influenced. Genes
Immun. 5: 513-516, 2004.
2. Reich, D.; Patterson, N.; Ramesh, V.; De Jager, P. L.; McDonald,
G. J.; Tandon, A.; Choy, E.; Hu, D.; Tamraz, B.; Pawlikowska, L.;
Wassel-Fyr, C.; Huntsman, S.; and 11 others: Admixture mapping
of an allele affecting interleukin 6 soluble receptor and interleukin
6 levels. Am. J. Hum. Genet. 80: 716-726, 2007.
*FIELD* CN
Paul J. Converse - updated: 8/1/2012
*FIELD* CD
Matthew B. Gross: 8/1/2012
*FIELD* ED
mgross: 08/01/2012
mgross: 8/1/2012