ID IL6_HUMAN Reviewed; 212 AA.
AC P05231; Q9UCU2; Q9UCU3; Q9UCU4;
DT 13-AUG-1987, integrated into UniProtKB/Swiss-Prot.
DT 13-AUG-1987, sequence version 1.
DT 28-JUN-2023, entry version 245.
DE RecName: Full=Interleukin-6 {ECO:0000305};
DE Short=IL-6;
DE AltName: Full=B-cell stimulatory factor 2;
DE Short=BSF-2;
DE AltName: Full=CTL differentiation factor;
DE Short=CDF;
DE AltName: Full=Hybridoma growth factor;
DE AltName: Full=Interferon beta-2;
DE Short=IFN-beta-2;
DE Flags: Precursor;
GN Name=IL6 {ECO:0000312|HGNC:HGNC:6018}; Synonyms=IFNB2;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND PARTIAL PROTEIN SEQUENCE.
RX PubMed=3491322; DOI=10.1038/324073a0;
RA Hirano T., Yasukawa K., Harada H., Taga T., Watanabe Y., Matsuda T.,
RA Kashiwamura S., Nakajima K., Koyama K., Iwamatsu A., Tsunasawa S.,
RA Sakiyama F., Matsui H., Takahara Y., Taniguchi T., Kishimoto T.;
RT "Complementary DNA for a novel human interleukin (BSF-2) that induces B
RT lymphocytes to produce immunoglobulin.";
RL Nature 324:73-76(1986).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=3500852; DOI=10.1002/j.1460-2075.1987.tb02598.x;
RA Yasukawa K., Hirano T., Watanabe Y., Muratani K., Matsuda T., Nakai S.,
RA Kishimoto T.;
RT "Structure and expression of human B cell stimulatory factor-2 (BSF-2/IL-6)
RT gene.";
RL EMBO J. 6:2939-2945(1987).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=3538015; DOI=10.1073/pnas.83.23.8957;
RA May L.T., Helfgott D.C., Sehgal P.B.;
RT "Anti-beta-interferon antibodies inhibit the increased expression of HLA-B7
RT mRNA in tumor necrosis factor-treated human fibroblasts: structural studies
RT of the beta 2 interferon involved.";
RL Proc. Natl. Acad. Sci. U.S.A. 83:8957-8961(1986).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=3023045; DOI=10.1002/j.1460-2075.1986.tb04531.x;
RA Zilberstein A., Ruggieri R., Korn J.H., Revel M.;
RT "Structure and expression of cDNA and genes for human interferon-beta-2, a
RT distinct species inducible by growth-stimulatory cytokines.";
RL EMBO J. 5:2529-2537(1986).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=3320204;
RA Brakenhoff J.P.J., de Groot E.R., Evers R.F., Pannekoek H., Aarden L.A.;
RT "Molecular cloning and expression of hybridoma growth factor in Escherichia
RT coli.";
RL J. Immunol. 139:4116-4121(1987).
RN [6]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=2789513; DOI=10.1016/0006-291x(89)92328-0;
RA Tonouchi N., Miwa K., Karasuyama H., Matsui H.;
RT "Deletion of 3' untranslated region of human BSF-2 mRNA causes
RT stabilization of the mRNA and high-level expression in mouse NIH3T3
RT cells.";
RL Biochem. Biophys. Res. Commun. 163:1056-1062(1989).
RN [7]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA].
RC TISSUE=Fibroblast;
RX PubMed=3758081; DOI=10.1111/j.1432-1033.1986.tb09931.x;
RA Haegeman G., Content J., Volckaert G., Derynck R., Tavernier J., Fiers W.;
RT "Structural analysis of the sequence coding for an inducible 26-kDa protein
RT in human fibroblasts.";
RL Eur. J. Biochem. 159:625-632(1986).
RN [8]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=3266463;
RA Wong G., Witek-Giannotti J., Hewick R., Clark S., Ogawa M.;
RT "Interleukin 6: identification as a hematopoietic colony-stimulating
RT factor.";
RL Behring Inst. Mitt. 83:40-47(1988).
RN [9]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=1291290;
RA Chen Q.Y.;
RT "Stable and efficient expression of human interleukin-6 cDNA in mammalian
RT cells after gene transfer.";
RL Zhonghua Zhong Liu Za Zhi 14:340-344(1992).
RN [10]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS SER-32 AND VAL-162.
RG SeattleSNPs variation discovery resource;
RL Submitted (JUN-2001) to the EMBL/GenBank/DDBJ databases.
RN [11]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Lung;
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 project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [12]
RP PROTEIN SEQUENCE OF 30-63.
RX PubMed=3279116;
RA van Damme J., van Beeumen J., Decock B., van Snick J., de Ley M.,
RA Billiau A.;
RT "Separation and comparison of two monokines with lymphocyte-activating
RT factor activity: IL-1 beta and hybridoma growth factor (HGF).
RT Identification of leukocyte-derived HGF as IL-6.";
RL J. Immunol. 140:1534-1541(1988).
RN [13]
RP PROTEIN SEQUENCE OF 30-50.
RX PubMed=2610854;
RA Ming J.E., Cernetti C., Steinman R.M., Granelli-Piperno A.;
RT "Interleukin 6 is the principal cytolytic T lymphocyte differentiation
RT factor for thymocytes in human leukocyte conditioned medium.";
RL J. Mol. Cell. Immunol. 4:203-211(1989).
RN [14]
RP PROTEIN SEQUENCE OF 30-40, AND GLYCOSYLATION.
RX PubMed=1883960; DOI=10.1016/1043-4666(91)90018-9;
RA May L.T., Shaw J.E., Khanna A.K., Zabriskie J.B., Sehgal P.B.;
RT "Marked cell-type-specific differences in glycosylation of human
RT interleukin-6.";
RL Cytokine 3:204-211(1991).
RN [15]
RP PROTEIN SEQUENCE OF 50-212.
RX PubMed=7851440; DOI=10.1111/j.1432-1033.1995.tb20427.x;
RA Breton J., la Fiura A., Bertolero F., Orsini G., Valsasina B., Ziliotto R.,
RA de Filippis V., Polverino de Laureto P., Fontana A.;
RT "Structure, stability and biological properties of a N-terminally truncated
RT form of recombinant human interleukin-6 containing a single disulfide
RT bond.";
RL Eur. J. Biochem. 227:573-581(1995).
RN [16]
RP DISULFIDE BONDS.
RX PubMed=2472117; DOI=10.1016/0003-9861(89)90205-1;
RA Clogston C.L., Boone T.C., Crandall B.C., Mendiaz E.A., Lu H.S.;
RT "Disulfide structures of human interleukin-6 are similar to those of human
RT granulocyte colony stimulating factor.";
RL Arch. Biochem. Biophys. 272:144-151(1989).
RN [17]
RP MUTAGENESIS.
RX PubMed=2037043; DOI=10.1016/0014-5793(91)80491-k;
RA Luetticken C., Kruettgen A., Moeller C., Heinrich P.C., Rose-John S.;
RT "Evidence for the importance of a positive charge and an alpha-helical
RT structure of the C-terminus for biological activity of human IL-6.";
RL FEBS Lett. 282:265-267(1991).
RN [18]
RP TISSUE SPECIFICITY, INDUCTION BY EXERCISE, AND SUBCELLULAR LOCATION.
RX PubMed=11080265; DOI=10.1111/j.1469-7793.2000.00237.x;
RA Steensberg A., van Hall G., Osada T., Sacchetti M., Saltin B.,
RA Klarlund Pedersen B.;
RT "Production of interleukin-6 in contracting human skeletal muscles can
RT account for the exercise-induced increase in plasma interleukin-6.";
RL J. Physiol. (Lond.) 529:237-242(2000).
RN [19]
RP FUNCTION.
RX PubMed=12794819; DOI=10.1002/art.11143;
RA Nakahara H., Song J., Sugimoto M., Hagihara K., Kishimoto T., Yoshizaki K.,
RA Nishimoto N.;
RT "Anti-interleukin-6 receptor antibody therapy reduces vascular endothelial
RT growth factor production in rheumatoid arthritis.";
RL Arthritis Rheum. 48:1521-1529(2003).
RN [20]
RP FUNCTION.
RX PubMed=15124018; DOI=10.1172/jci20945;
RA Nemeth E., Rivera S., Gabayan V., Keller C., Taudorf S., Pedersen B.K.,
RA Ganz T.;
RT "IL-6 mediates hypoferremia of inflammation by inducing the synthesis of
RT the iron regulatory hormone hepcidin.";
RL J. Clin. Invest. 113:1271-1276(2004).
RN [21]
RP FUNCTION.
RX PubMed=17075861; DOI=10.1002/art.22175;
RA De Benedetti F., Rucci N., Del Fattore A., Peruzzi B., Paro R., Longo M.,
RA Vivarelli M., Muratori F., Berni S., Ballanti P., Ferrari S., Teti A.;
RT "Impaired skeletal development in interleukin-6-transgenic mice: a model
RT for the impact of chronic inflammation on the growing skeletal system.";
RL Arthritis Rheum. 54:3551-3563(2006).
RN [22]
RP FUNCTION.
RX PubMed=20823453; DOI=10.1152/ajpendo.00328.2010;
RA Wolsk E., Mygind H., Groendahl T.S., Pedersen B.K., van Hall G.;
RT "IL-6 selectively stimulates fat metabolism in human skeletal muscle.";
RL Am. J. Physiol. 299:E832-E840(2010).
RN [23]
RP FUNCTION.
RX PubMed=22037645; DOI=10.1038/nm.2513;
RA Ellingsgaard H., Hauselmann I., Schuler B., Habib A.M., Baggio L.L.,
RA Meier D.T., Eppler E., Bouzakri K., Wueest S., Muller Y.D., Hansen A.M.,
RA Reinecke M., Konrad D., Gassmann M., Reimann F., Halban P.A., Gromada J.,
RA Drucker D.J., Gribble F.M., Ehses J.A., Donath M.Y.;
RT "Interleukin-6 enhances insulin secretion by increasing glucagon-like
RT peptide-1 secretion from L cells and alpha cells.";
RL Nat. Med. 17:1481-1489(2011).
RN [24]
RP PHOSPHORYLATION AT SER-81.
RX PubMed=26091039; DOI=10.1016/j.cell.2015.05.028;
RA Tagliabracci V.S., Wiley S.E., Guo X., Kinch L.N., Durrant E., Wen J.,
RA Xiao J., Cui J., Nguyen K.B., Engel J.L., Coon J.J., Grishin N.,
RA Pinna L.A., Pagliarini D.J., Dixon J.E.;
RT "A single kinase generates the majority of the secreted phosphoproteome.";
RL Cell 161:1619-1632(2015).
RN [25]
RP FUNCTION.
RX PubMed=25731159; DOI=10.1038/nature14228;
RA Taniguchi K., Wu L.W., Grivennikov S.I., de Jong P.R., Lian I., Yu F.X.,
RA Wang K., Ho S.B., Boland B.S., Chang J.T., Sandborn W.J., Hardiman G.,
RA Raz E., Maehara Y., Yoshimura A., Zucman-Rossi J., Guan K.L., Karin M.;
RT "A gp130-Src-YAP module links inflammation to epithelial regeneration.";
RL Nature 519:57-62(2015).
RN [26]
RP INTERACTION WITH IL6R AND SORL1.
RX PubMed=28265003; DOI=10.1128/mcb.00641-16;
RA Larsen J.V., Petersen C.M.;
RT "SorLA in Interleukin-6 Signaling and Turnover.";
RL Mol. Cell. Biol. 37:0-0(2017).
RN [27]
RP REVIEW ON FUNCTION.
RX PubMed=30995492; DOI=10.1016/j.immuni.2019.03.026;
RA Kang S., Tanaka T., Narazaki M., Kishimoto T.;
RT "Targeting Interleukin-6 Signaling in Clinic.";
RL Immunity 50:1007-1023(2019).
RN [28]
RP STRUCTURE BY NMR.
RX PubMed=8555185; DOI=10.1021/bi951949e;
RA Nishimura C., Watanabe A., Gouda H., Shimada I., Arata Y.;
RT "Folding topologies of human interleukin-6 and its mutants as studied by
RT NMR spectroscopy.";
RL Biochemistry 35:273-281(1996).
RN [29]
RP STRUCTURE BY NMR.
RX PubMed=9159484; DOI=10.1006/jmbi.1997.0933;
RA Xu G.-Y., Yu H.-A., Hong J., Stahl M., McDonagh T., Kay L.E., Cumming D.A.;
RT "Solution structure of recombinant human interleukin-6.";
RL J. Mol. Biol. 268:468-481(1997).
RN [30]
RP X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS).
RX PubMed=9118960; DOI=10.1093/emboj/16.5.989;
RA Somers W., Stahl M., Seehra J.S.;
RT "1.9-A crystal structure of interleukin 6: implications for a novel mode of
RT receptor dimerization and signaling.";
RL EMBO J. 16:989-997(1997).
RN [31] {ECO:0007744|PDB:1P9M}
RP X-RAY CRYSTALLOGRAPHY (3.65 ANGSTROMS) OF 29-212 IN COMPLEX WITH IL6ST AND
RP IL6R, AND SUBUNIT.
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 [32]
RP INVOLVEMENT IN RASJ.
RX PubMed=9769329; DOI=10.1172/jci2629;
RA Fishman D., Faulds G., Jeffery R., Mohamed-Ali V., Yudkin J.S.,
RA Humphries S., Woo P.;
RT "The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6
RT transcription and plasma IL-6 levels, and an association with systemic-
RT onset juvenile chronic arthritis.";
RL J. Clin. Invest. 102:1369-1376(1998).
RN [33]
RP INVOLVEMENT IN SUSCEPTIBILITY TO KAPOSI SARCOMA.
RX PubMed=11001912;
RA Foster C.B., Lehrnbecher T., Samuels S., Stein S., Mol F., Metcalf J.A.,
RA Wyvill K., Steinberg S.M., Kovacs J., Blauvelt A., Yarchoan R.,
RA Chanock S.J.;
RT "An IL6 promoter polymorphism is associated with a lifetime risk of
RT development of Kaposi sarcoma in men infected with human immunodeficiency
RT virus.";
RL Blood 96:2562-2567(2000).
RN [34]
RP INVOLVEMENT IN BMD.
RX PubMed=11355017; DOI=10.1007/s100380170077;
RA Ota N., Nakajima T., Nakazawa I., Suzuki T., Hosoi T., Orimo H., Inoue S.,
RA Shirai Y., Emi M.;
RT "A nucleotide variant in the promoter region of the interleukin-6 gene
RT associated with decreased bone mineral density.";
RL J. Hum. Genet. 46:267-272(2001).
RN [35]
RP INVOLVEMENT IN BMD.
RX PubMed=12768442; DOI=10.1007/s10038-003-0020-8;
RA Chung H.W., Seo J.-S., Hur S.E., Kim H.L., Kim J.Y., Jung J.H., Kim L.H.,
RA Park B.L., Shin H.D.;
RT "Association of interleukin-6 promoter variant with bone mineral density in
RT pre-menopausal women.";
RL J. Hum. Genet. 48:243-248(2003).
CC -!- FUNCTION: Cytokine with a wide variety of biological functions in
CC immunity, tissue regeneration, and metabolism. Binds to IL6R, then the
CC complex associates to the signaling subunit IL6ST/gp130 to trigger the
CC intracellular IL6-signaling pathway (Probable). The interaction with
CC the membrane-bound IL6R and IL6ST stimulates 'classic signaling',
CC whereas the binding of IL6 and soluble IL6R to IL6ST stimulates 'trans-
CC signaling'. Alternatively, 'cluster signaling' occurs when membrane-
CC bound IL6:IL6R complexes on transmitter cells activate IL6ST receptors
CC on neighboring receiver cells (Probable).
CC {ECO:0000305|PubMed:30995492}.
CC -!- FUNCTION: IL6 is a potent inducer of the acute phase response. Rapid
CC production of IL6 contributes to host defense during infection and
CC tissue injury, but excessive IL6 synthesis is involved in disease
CC pathology. In the innate immune response, is synthesized by myeloid
CC cells, such as macrophages and dendritic cells, upon recognition of
CC pathogens through toll-like receptors (TLRs) at the site of infection
CC or tissue injury (Probable). In the adaptive immune response, is
CC required for the differentiation of B cells into immunoglobulin-
CC secreting cells. Plays a major role in the differentiation of CD4(+) T
CC cell subsets. Essential factor for the development of T follicular
CC helper (Tfh) cells that are required for the induction of germinal-
CC center formation. Required to drive naive CD4(+) T cells to the Th17
CC lineage. Also required for proliferation of myeloma cells and the
CC survival of plasmablast cells (By similarity).
CC {ECO:0000250|UniProtKB:P08505, ECO:0000305|PubMed:30995492}.
CC -!- FUNCTION: Acts as an essential factor in bone homeostasis and on
CC vessels directly or indirectly by induction of VEGF, resulting in
CC increased angiogenesis activity and vascular permeability
CC (PubMed:17075861, PubMed:12794819). Induces, through 'trans-signaling'
CC and synergistically with IL1B and TNF, the production of VEGF
CC (PubMed:12794819). Involved in metabolic controls, is discharged into
CC the bloodstream after muscle contraction increasing lipolysis and
CC improving insulin resistance (PubMed:20823453). 'Trans-signaling' in
CC central nervous system also regulates energy and glucose homeostasis
CC (By similarity). Mediates, through GLP-1, crosstalk between insulin-
CC sensitive tissues, intestinal L cells and pancreatic islets to adapt to
CC changes in insulin demand (By similarity). Also acts as a myokine
CC (Probable). Plays a protective role during liver injury, being required
CC for maintenance of tissue regeneration (By similarity). Also has a
CC pivotal role in iron metabolism by regulating HAMP/hepcidin expression
CC upon inflammation or bacterial infection (PubMed:15124018). Through
CC activation of IL6ST-YAP-NOTCH pathway, induces inflammation-induced
CC epithelial regeneration (By similarity). {ECO:0000250|UniProtKB:P08505,
CC ECO:0000269|PubMed:12794819, ECO:0000269|PubMed:15124018,
CC ECO:0000269|PubMed:17075861, ECO:0000269|PubMed:20823453,
CC ECO:0000305|PubMed:30995492}.
CC -!- SUBUNIT: Component of a hexamer of two molecules each of IL6, IL6R and
CC IL6ST; first binds to IL6R to associate with the signaling subunit
CC IL6ST (PubMed:12829785). Interacts with IL6R (via the N-terminal
CC ectodomain); this interaction may be affected by IL6R-binding with
CC SORL1, hence decreasing IL6 cis signaling (PubMed:28265003). Interacts
CC with SORL1 (via the N-terminal ectodomain); this interaction leads to
CC IL6 internalization and lysosomal degradation (PubMed:28265003). May
CC form a trimeric complex with the soluble SORL1 ectodomain and soluble
CC IL6R receptor; this interaction might stabilize circulating IL6, hence
CC promoting IL6 trans signaling (PubMed:28265003).
CC {ECO:0000269|PubMed:12829785, ECO:0000269|PubMed:28265003}.
CC -!- INTERACTION:
CC P05231; P08887: IL6R; NbExp=7; IntAct=EBI-720533, EBI-299383;
CC P05231; Q92673: SORL1; NbExp=4; IntAct=EBI-720533, EBI-1171329;
CC P05231; Q99523: SORT1; NbExp=4; IntAct=EBI-720533, EBI-1057058;
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:11080265}.
CC -!- TISSUE SPECIFICITY: Produced by skeletal muscle.
CC {ECO:0000269|PubMed:11080265}.
CC -!- INDUCTION: Plasma levels are highly increased upon exercise, due to
CC enhanced production by contracting skeletal muscles.
CC {ECO:0000269|PubMed:11080265}.
CC -!- PTM: N- and O-glycosylated. {ECO:0000269|PubMed:1883960}.
CC -!- POLYMORPHISM: Genetic variations in IL6 may be correlated with bone
CC mineral density (BMD). Low BMD is a risk factor for osteoporotic
CC fracture. Osteoporosis is characterized by reduced bone mineral
CC density, disruption of bone microarchitecture, and the alteration of
CC the amount and variety of non-collagenous proteins in bone.
CC Osteoporotic bones are more at risk of fracture.
CC {ECO:0000269|PubMed:11355017, ECO:0000269|PubMed:12768442}.
CC -!- DISEASE: Rheumatoid arthritis systemic juvenile (RASJ) [MIM:604302]: An
CC inflammatory articular disorder with systemic onset beginning before
CC the age of 16. It represents a subgroup of juvenile arthritis
CC associated with severe extraarticular features and occasionally fatal
CC complications. During active phases of the disorder, patients display a
CC typical daily spiking fever, an evanescent macular rash,
CC lymphadenopathy, hepatosplenomegaly, serositis, myalgia and arthritis.
CC {ECO:0000269|PubMed:9769329}. Note=Disease susceptibility is associated
CC with variants affecting the gene represented in this entry.
CC -!- DISEASE: Note=A IL6 promoter polymorphism is associated with a lifetime
CC risk of development of Kaposi sarcoma in HIV-infected men.
CC {ECO:0000269|PubMed:11001912}.
CC -!- SIMILARITY: Belongs to the IL-6 superfamily. {ECO:0000305}.
CC -!- WEB RESOURCE: Name=Wikipedia; Note=Interleukin-6 entry;
CC URL="https://en.wikipedia.org/wiki/Interleukin_6";
CC -!- WEB RESOURCE: Name=SeattleSNPs;
CC URL="http://pga.gs.washington.edu/data/il6/";
CC -!- WEB RESOURCE: Name=SHMPD; Note=The Singapore human mutation and
CC polymorphism database;
CC URL="http://shmpd.bii.a-star.edu.sg/gene.php?genestart=A&genename=IL6";
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and
CC Haematology;
CC URL="https://atlasgeneticsoncology.org/gene/519/IL6";
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DR EMBL; X04430; CAA28026.1; -; mRNA.
DR EMBL; M14584; AAA52728.1; -; mRNA.
DR EMBL; X04602; CAA28268.1; -; mRNA.
DR EMBL; Y00081; CAA68278.1; -; Genomic_DNA.
DR EMBL; M18403; AAA52729.1; -; mRNA.
DR EMBL; M29150; AAA59154.1; -; mRNA.
DR EMBL; X04402; CAA27990.1; -; Genomic_DNA.
DR EMBL; X04403; CAA27991.1; -; mRNA.
DR EMBL; M54894; AAC41704.1; -; mRNA.
DR EMBL; S56892; AAD13886.1; -; mRNA.
DR EMBL; AF372214; AAK48987.1; -; Genomic_DNA.
DR EMBL; BC015511; AAH15511.1; -; mRNA.
DR CCDS; CCDS5375.1; -.
DR PIR; A32648; IVHUB2.
DR RefSeq; NP_000591.1; NM_000600.4.
DR RefSeq; XP_011513692.1; XM_011515390.2.
DR PDB; 1ALU; X-ray; 1.90 A; A=28-212.
DR PDB; 1IL6; NMR; -; A=28-212.
DR PDB; 1P9M; X-ray; 3.65 A; B=29-212.
DR PDB; 2IL6; NMR; -; A=28-212.
DR PDB; 4CNI; X-ray; 2.20 A; C/D=42-212.
DR PDB; 4J4L; X-ray; 2.30 A; C/D=47-212.
DR PDB; 4NI7; X-ray; 2.40 A; A=28-212.
DR PDB; 4NI9; X-ray; 2.55 A; A/C=28-212.
DR PDB; 4O9H; X-ray; 2.42 A; A=28-212.
DR PDB; 4ZS7; X-ray; 2.93 A; A=42-212.
DR PDB; 5FUC; X-ray; 2.70 A; A/B=49-212.
DR PDB; 7NXZ; X-ray; 2.00 A; AAA=30-212.
DR PDB; 8D82; EM; 3.22 A; D/H=30-212.
DR PDBsum; 1ALU; -.
DR PDBsum; 1IL6; -.
DR PDBsum; 1P9M; -.
DR PDBsum; 2IL6; -.
DR PDBsum; 4CNI; -.
DR PDBsum; 4J4L; -.
DR PDBsum; 4NI7; -.
DR PDBsum; 4NI9; -.
DR PDBsum; 4O9H; -.
DR PDBsum; 4ZS7; -.
DR PDBsum; 5FUC; -.
DR PDBsum; 7NXZ; -.
DR PDBsum; 8D82; -.
DR AlphaFoldDB; P05231; -.
DR SMR; P05231; -.
DR BioGRID; 109783; 11.
DR DIP; DIP-482N; -.
DR IntAct; P05231; 8.
DR STRING; 9606.ENSP00000385675; -.
DR BindingDB; P05231; -.
DR ChEMBL; CHEMBL1795129; -.
DR DrugBank; DB05767; Andrographolide.
DR DrugBank; DB05513; Atiprimod.
DR DrugBank; DB11967; Binimetinib.
DR DrugBank; DB05744; CRx-139.
DR DrugBank; DB12140; Dilmapimod.
DR DrugBank; DB10770; Foreskin fibroblast (neonatal).
DR DrugBank; DB10772; Foreskin keratinocyte (neonatal).
DR DrugBank; DB01404; Ginseng.
DR DrugBank; DB13127; Olokizumab.
DR DrugBank; DB09221; Polaprezinc.
DR DrugBank; DB09036; Siltuximab.
DR DrugBank; DB05470; VX-702.
DR DrugBank; DB05017; YSIL6.
DR DrugCentral; P05231; -.
DR GlyCosmos; P05231; 1 site, No reported glycans.
DR GlyGen; P05231; 2 sites.
DR iPTMnet; P05231; -.
DR MetOSite; P05231; -.
DR PhosphoSitePlus; P05231; -.
DR BioMuta; IL6; -.
DR DMDM; 124347; -.
DR MassIVE; P05231; -.
DR PaxDb; P05231; -.
DR PeptideAtlas; P05231; -.
DR ProteomicsDB; 51828; -.
DR ABCD; P05231; 187 sequenced antibodies.
DR Antibodypedia; 12025; 3277 antibodies from 50 providers.
DR CPTC; P05231; 3 antibodies.
DR DNASU; 3569; -.
DR Ensembl; ENST00000258743.10; ENSP00000258743.5; ENSG00000136244.12.
DR Ensembl; ENST00000404625.5; ENSP00000385675.1; ENSG00000136244.12.
DR GeneID; 3569; -.
DR KEGG; hsa:3569; -.
DR MANE-Select; ENST00000258743.10; ENSP00000258743.5; NM_000600.5; NP_000591.1.
DR AGR; HGNC:6018; -.
DR CTD; 3569; -.
DR DisGeNET; 3569; -.
DR GeneCards; IL6; -.
DR HGNC; HGNC:6018; IL6.
DR HPA; ENSG00000136244; Tissue enhanced (adipose tissue, urinary bladder).
DR MalaCards; IL6; -.
DR MIM; 147620; gene.
DR MIM; 148000; phenotype.
DR MIM; 604302; phenotype.
DR neXtProt; NX_P05231; -.
DR OpenTargets; ENSG00000136244; -.
DR Orphanet; 206; NON RARE IN EUROPE: Crohn disease.
DR Orphanet; 85414; Systemic-onset juvenile idiopathic arthritis.
DR PharmGKB; PA198; -.
DR VEuPathDB; HostDB:ENSG00000136244; -.
DR eggNOG; ENOG502S7Q4; Eukaryota.
DR GeneTree; ENSGT00390000000878; -.
DR InParanoid; P05231; -.
DR OMA; FSKCENS; -.
DR OrthoDB; 5352039at2759; -.
DR PhylomeDB; P05231; -.
DR TreeFam; TF335984; -.
DR PathwayCommons; P05231; -.
DR Reactome; R-HSA-1059683; Interleukin-6 signaling.
DR Reactome; R-HSA-110056; MAPK3 (ERK1) activation.
DR Reactome; R-HSA-112411; MAPK1 (ERK2) activation.
DR Reactome; R-HSA-2559582; Senescence-Associated Secretory Phenotype (SASP).
DR Reactome; R-HSA-381426; Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs).
DR Reactome; R-HSA-6783783; Interleukin-10 signaling.
DR Reactome; R-HSA-6785807; Interleukin-4 and Interleukin-13 signaling.
DR Reactome; R-HSA-8853884; Transcriptional Regulation by VENTX.
DR Reactome; R-HSA-8957275; Post-translational protein phosphorylation.
DR Reactome; R-HSA-9660821; ADORA2B mediated anti-inflammatory cytokines production.
DR Reactome; R-HSA-9662834; CD163 mediating an anti-inflammatory response.
DR SignaLink; P05231; -.
DR SIGNOR; P05231; -.
DR BioGRID-ORCS; 3569; 8 hits in 1164 CRISPR screens.
DR ChiTaRS; IL6; human.
DR EvolutionaryTrace; P05231; -.
DR GeneWiki; Interleukin_6; -.
DR GenomeRNAi; 3569; -.
DR Pharos; P05231; Tclin.
DR PRO; PR:P05231; -.
DR Proteomes; UP000005640; Chromosome 7.
DR RNAct; P05231; protein.
DR Bgee; ENSG00000136244; Expressed in cartilage tissue and 127 other tissues.
DR ExpressionAtlas; P05231; baseline and differential.
DR Genevisible; P05231; HS.
DR GO; GO:0005788; C:endoplasmic reticulum lumen; TAS:Reactome.
DR GO; GO:0005576; C:extracellular region; TAS:Reactome.
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:0005125; F:cytokine activity; IDA:BHF-UCL.
DR GO; GO:0008083; F:growth factor activity; IDA:BHF-UCL.
DR GO; GO:0005138; F:interleukin-6 receptor binding; IPI:BHF-UCL.
DR GO; GO:0006953; P:acute-phase response; TAS:BHF-UCL.
DR GO; GO:0070301; P:cellular response to hydrogen peroxide; IDA:BHF-UCL.
DR GO; GO:0071222; P:cellular response to lipopolysaccharide; IMP:MGI.
DR GO; GO:0098586; P:cellular response to virus; ISS:UniProtKB.
DR GO; GO:0019221; P:cytokine-mediated signaling pathway; IDA:BHF-UCL.
DR GO; GO:0050829; P:defense response to Gram-negative bacterium; TAS:BHF-UCL.
DR GO; GO:0050830; P:defense response to Gram-positive bacterium; TAS:BHF-UCL.
DR GO; GO:0051607; P:defense response to virus; IDA:BHF-UCL.
DR GO; GO:0031018; P:endocrine pancreas development; ISS:BHF-UCL.
DR GO; GO:0002314; P:germinal center B cell differentiation; ISS:UniProtKB.
DR GO; GO:0070091; P:glucagon secretion; ISS:BHF-UCL.
DR GO; GO:0042593; P:glucose homeostasis; IDA:UniProtKB.
DR GO; GO:0002384; P:hepatic immune response; IDA:BHF-UCL.
DR GO; GO:0072574; P:hepatocyte proliferation; ISS:UniProtKB.
DR GO; GO:0006959; P:humoral immune response; IC:BHF-UCL.
DR GO; GO:0006954; P:inflammatory response; IDA:BHF-UCL.
DR GO; GO:0090594; P:inflammatory response to wounding; IDA:UniProt.
DR GO; GO:0070102; P:interleukin-6-mediated signaling pathway; IDA:BHF-UCL.
DR GO; GO:0097421; P:liver regeneration; ISS:UniProtKB.
DR GO; GO:0035633; P:maintenance of blood-brain barrier; TAS:ARUK-UCL.
DR GO; GO:0002548; P:monocyte chemotaxis; IC:BHF-UCL.
DR GO; GO:0043066; P:negative regulation of apoptotic process; IDA:UniProtKB.
DR GO; GO:0045779; P:negative regulation of bone resorption; ISS:BHF-UCL.
DR GO; GO:0008285; P:negative regulation of cell population proliferation; TAS:ProtInc.
DR GO; GO:0032682; P:negative regulation of chemokine production; ISS:UniProtKB.
DR GO; GO:0032966; P:negative regulation of collagen biosynthetic process; IDA:BHF-UCL.
DR GO; GO:0045599; P:negative regulation of fat cell differentiation; NAS:BHF-UCL.
DR GO; GO:2000660; P:negative regulation of interleukin-1-mediated signaling pathway; ISS:BHF-UCL.
DR GO; GO:0010888; P:negative regulation of lipid storage; NAS:BHF-UCL.
DR GO; GO:0050768; P:negative regulation of neurogenesis; TAS:ARUK-UCL.
DR GO; GO:2000635; P:negative regulation of primary miRNA processing; IGI:ARUK-UCL.
DR GO; GO:0070050; P:neuron cellular homeostasis; TAS:ARUK-UCL.
DR GO; GO:0031175; P:neuron projection development; IMP:BHF-UCL.
DR GO; GO:0001781; P:neutrophil apoptotic process; IDA:UniProtKB.
DR GO; GO:0002446; P:neutrophil mediated immunity; TAS:BHF-UCL.
DR GO; GO:0030168; P:platelet activation; TAS:BHF-UCL.
DR GO; GO:0002675; P:positive regulation of acute inflammatory response; IDA:BHF-UCL.
DR GO; GO:1902512; P:positive regulation of apoptotic DNA fragmentation; IMP:ARUK-UCL.
DR GO; GO:0043065; P:positive regulation of apoptotic process; IDA:UniProtKB.
DR GO; GO:0050871; P:positive regulation of B cell activation; IDA:BHF-UCL.
DR GO; GO:0008284; P:positive regulation of cell population proliferation; IDA:BHF-UCL.
DR GO; GO:0032722; P:positive regulation of chemokine production; IDA:BHF-UCL.
DR GO; GO:1900017; P:positive regulation of cytokine production involved in inflammatory response; IGI:ARUK-UCL.
DR GO; GO:0051091; P:positive regulation of DNA-binding transcription factor activity; IDA:ARUK-UCL.
DR GO; GO:0045893; P:positive regulation of DNA-templated transcription; IDA:UniProtKB.
DR GO; GO:0010718; P:positive regulation of epithelial to mesenchymal transition; IDA:ARUK-UCL.
DR GO; GO:0090091; P:positive regulation of extracellular matrix disassembly; IMP:ARUK-UCL.
DR GO; GO:0010628; P:positive regulation of gene expression; IDA:BHF-UCL.
DR GO; GO:0060252; P:positive regulation of glial cell proliferation; IDA:ARUK-UCL.
DR GO; GO:0002639; P:positive regulation of immunoglobulin production; IDA:BHF-UCL.
DR GO; GO:0032731; P:positive regulation of interleukin-1 beta production; IGI:ARUK-UCL.
DR GO; GO:0032733; P:positive regulation of interleukin-10 production; IDA:ARUK-UCL.
DR GO; GO:0032740; P:positive regulation of interleukin-17 production; ISS:ARUK-UCL.
DR GO; GO:0032745; P:positive regulation of interleukin-21 production; ISS:UniProtKB.
DR GO; GO:0032755; P:positive regulation of interleukin-6 production; IDA:BHF-UCL.
DR GO; GO:0032757; P:positive regulation of interleukin-8 production; IDA:ARUK-UCL.
DR GO; GO:1904996; P:positive regulation of leukocyte adhesion to vascular endothelial cell; IDA:ARUK-UCL.
DR GO; GO:0002690; P:positive regulation of leukocyte chemotaxis; TAS:BHF-UCL.
DR GO; GO:0043410; P:positive regulation of MAPK cascade; IDA:BHF-UCL.
DR GO; GO:0150078; P:positive regulation of neuroinflammatory response; TAS:ARUK-UCL.
DR GO; GO:0045669; P:positive regulation of osteoblast differentiation; IDA:ARUK-UCL.
DR GO; GO:0033138; P:positive regulation of peptidyl-serine phosphorylation; IDA:MGI.
DR GO; GO:0050731; P:positive regulation of peptidyl-tyrosine phosphorylation; IDA:MGI.
DR GO; GO:1901731; P:positive regulation of platelet aggregation; IDA:ARUK-UCL.
DR GO; GO:0046427; P:positive regulation of receptor signaling pathway via JAK-STAT; IDA:BHF-UCL.
DR GO; GO:1904894; P:positive regulation of receptor signaling pathway via STAT; IGI:ARUK-UCL.
DR GO; GO:0048661; P:positive regulation of smooth muscle cell proliferation; IDA:BHF-UCL.
DR GO; GO:0042102; P:positive regulation of T cell proliferation; IDA:BHF-UCL.
DR GO; GO:2000553; P:positive regulation of T-helper 2 cell cytokine production; ISS:BHF-UCL.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:BHF-UCL.
DR GO; GO:0045727; P:positive regulation of translation; IDA:UniProtKB.
DR GO; GO:0032760; P:positive regulation of tumor necrosis factor production; IDA:ARUK-UCL.
DR GO; GO:2000676; P:positive regulation of type B pancreatic cell apoptotic process; TAS:BHF-UCL.
DR GO; GO:0042531; P:positive regulation of tyrosine phosphorylation of STAT protein; IDA:BHF-UCL.
DR GO; GO:0010575; P:positive regulation of vascular endothelial growth factor production; IMP:ARUK-UCL.
DR GO; GO:0045765; P:regulation of angiogenesis; IC:BHF-UCL.
DR GO; GO:0061888; P:regulation of astrocyte activation; TAS:ARUK-UCL.
DR GO; GO:0070092; P:regulation of glucagon secretion; IDA:UniProtKB.
DR GO; GO:0050796; P:regulation of insulin secretion; IDA:UniProtKB.
DR GO; GO:1903978; P:regulation of microglial cell activation; TAS:ARUK-UCL.
DR GO; GO:0150077; P:regulation of neuroinflammatory response; TAS:ARUK-UCL.
DR GO; GO:0010574; P:regulation of vascular endothelial growth factor production; IDA:BHF-UCL.
DR GO; GO:0014823; P:response to activity; ISS:UniProtKB.
DR GO; GO:0051384; P:response to glucocorticoid; IDA:BHF-UCL.
DR GO; GO:0032494; P:response to peptidoglycan; NAS:BHF-UCL.
DR GO; GO:0061470; P:T follicular helper cell differentiation; ISS:UniProtKB.
DR GO; GO:0072540; P:T-helper 17 cell lineage commitment; ISS:UniProtKB.
DR GO; GO:0010573; P:vascular endothelial growth factor production; IDA:UniProtKB.
DR DisProt; DP02745; -.
DR Gene3D; 1.20.1250.10; -; 1.
DR InterPro; IPR009079; 4_helix_cytokine-like_core.
DR InterPro; IPR003574; IL-6.
DR InterPro; IPR030474; IL-6/GCSF/MGF.
DR InterPro; IPR030473; IL6/GCSF/MGF_CS.
DR PANTHER; PTHR10511; GRANULOCYTE COLONY-STIMULATING FACTOR; 1.
DR PANTHER; PTHR10511:SF3; INTERLEUKIN-6; 1.
DR Pfam; PF00489; IL6; 1.
DR PIRSF; PIRSF001935; IL6_MGF_GCSF; 1.
DR PRINTS; PR00433; IL6GCSFMGF.
DR PRINTS; PR00434; INTERLEUKIN6.
DR SMART; SM00126; IL6; 1.
DR SUPFAM; SSF47266; 4-helical cytokines; 1.
DR PROSITE; PS00254; INTERLEUKIN_6; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acute phase; Cytokine; Direct protein sequencing;
KW Disulfide bond; Glycoprotein; Growth factor; Phosphoprotein;
KW Reference proteome; Secreted; Signal.
FT SIGNAL 1..29
FT /evidence="ECO:0000269|PubMed:1883960,
FT ECO:0000269|PubMed:2610854, ECO:0000269|PubMed:3279116"
FT CHAIN 30..212
FT /note="Interleukin-6"
FT /id="PRO_0000015582"
FT MOD_RES 81
FT /note="Phosphoserine; by FAM20C"
FT /evidence="ECO:0000269|PubMed:26091039"
FT CARBOHYD 73
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:1883960"
FT DISULFID 72..78
FT /evidence="ECO:0000269|PubMed:2472117"
FT DISULFID 101..111
FT /evidence="ECO:0000269|PubMed:2472117"
FT VARIANT 32
FT /note="P -> S (in dbSNP:rs2069830)"
FT /evidence="ECO:0000269|Ref.10"
FT /id="VAR_013075"
FT VARIANT 162
FT /note="D -> E (in dbSNP:rs13306435)"
FT /id="VAR_029266"
FT VARIANT 162
FT /note="D -> V (in dbSNP:rs2069860)"
FT /evidence="ECO:0000269|Ref.10"
FT /id="VAR_013076"
FT MUTAGEN 173
FT /note="A->V: Almost no loss of activity."
FT /evidence="ECO:0000269|PubMed:2037043"
FT MUTAGEN 185
FT /note="W->R: No loss of activity."
FT /evidence="ECO:0000269|PubMed:2037043"
FT MUTAGEN 204
FT /note="S->P: 87% loss of activity."
FT /evidence="ECO:0000269|PubMed:2037043"
FT MUTAGEN 210
FT /note="R->K,E,Q,T,A,P: Loss of activity."
FT /evidence="ECO:0000269|PubMed:2037043"
FT MUTAGEN 212
FT /note="M->T,N,S,R: Loss of activity."
FT /evidence="ECO:0000269|PubMed:2037043"
FT HELIX 49..75
FT /evidence="ECO:0007829|PDB:1ALU"
FT STRAND 76..79
FT /evidence="ECO:0007829|PDB:2IL6"
FT TURN 81..83
FT /evidence="ECO:0007829|PDB:4CNI"
FT HELIX 84..87
FT /evidence="ECO:0007829|PDB:4CNI"
FT HELIX 97..99
FT /evidence="ECO:0007829|PDB:1ALU"
FT STRAND 102..105
FT /evidence="ECO:0007829|PDB:4J4L"
FT HELIX 108..132
FT /evidence="ECO:0007829|PDB:1ALU"
FT STRAND 134..136
FT /evidence="ECO:0007829|PDB:4J4L"
FT HELIX 137..157
FT /evidence="ECO:0007829|PDB:1ALU"
FT STRAND 159..161
FT /evidence="ECO:0007829|PDB:1ALU"
FT HELIX 169..180
FT /evidence="ECO:0007829|PDB:1ALU"
FT HELIX 184..209
FT /evidence="ECO:0007829|PDB:1ALU"
SQ SEQUENCE 212 AA; 23718 MW; 1F1ED1FE1B734079 CRC64;
MNSFSTSAFG PVAFSLGLLL VLPAAFPAPV PPGEDSKDVA APHRQPLTSS ERIDKQIRYI
LDGISALRKE TCNKSNMCES SKEALAENNL NLPKMAEKDG CFQSGFNEET CLVKIITGLL
EFEVYLEYLQ NRFESSEEQA RAVQMSTKVL IQFLQKKAKN LDAITTPDPT TNASLLTKLQ
AQNQWLQDMT THLILRSFKE FLQSSLRALR QM
//