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   12-AUG-2020, entry version 231.
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:0000244|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       P05231; Q05516: ZBTB16; NbExp=2; IntAct=EBI-720533, EBI-711925;
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 variations 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="http://atlasgeneticsoncology.org/Genes/IL6ID519ch7p15.html";
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; 1N2Q; Model; -; E/F=30-212.
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   PDBsum; 1ALU; -.
DR   PDBsum; 1IL6; -.
DR   PDBsum; 1N2Q; -.
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   SMR; P05231; -.
DR   BioGRID; 109783; 5.
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; DB09221; Polaprezinc.
DR   DrugBank; DB09036; Siltuximab.
DR   DrugBank; DB06083; Tapinarof.
DR   DrugBank; DB05470; VX-702.
DR   DrugBank; DB05017; YSIL6.
DR   DrugCentral; P05231; -.
DR   GlyGen; P05231; 1 site.
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   PRIDE; P05231; -.
DR   ProteomicsDB; 51828; -.
DR   ABCD; P05231; 181 sequenced antibodies.
DR   Antibodypedia; 12025; 2741 antibodies.
DR   DNASU; 3569; -.
DR   Ensembl; ENST00000258743; ENSP00000258743; ENSG00000136244.
DR   Ensembl; ENST00000404625; ENSP00000385675; ENSG00000136244.
DR   GeneID; 3569; -.
DR   KEGG; hsa:3569; -.
DR   CTD; 3569; -.
DR   DisGeNET; 3569; -.
DR   EuPathDB; HostDB:ENSG00000136244.11; -.
DR   GeneCards; IL6; -.
DR   HGNC; HGNC:6018; IL6.
DR   HPA; ENSG00000136244; Tissue enhanced (adipose tissue, lymphoid tissue).
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   eggNOG; ENOG502S7Q4; Eukaryota.
DR   GeneTree; ENSGT00390000000878; -.
DR   InParanoid; P05231; -.
DR   KO; K05405; -.
DR   OMA; YDKCENS; -.
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; 4 hits in 872 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 left coronary artery and 159 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:0044267; P:cellular protein metabolic process; TAS:Reactome.
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: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:0070091; P:glucagon secretion; ISS:BHF-UCL.
DR   GO; GO:0002384; P:hepatic immune response; IDA:BHF-UCL.
DR   GO; GO:0006959; P:humoral immune response; IC:BHF-UCL.
DR   GO; GO:0006954; P:inflammatory response; IDA:BHF-UCL.
DR   GO; GO:0070102; P:interleukin-6-mediated signaling pathway; IDA:BHF-UCL.
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:0045079; P:negative regulation of chemokine biosynthetic process; 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: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:0051024; P:positive regulation of immunoglobulin secretion; IDA:BHF-UCL.
DR   GO; GO:0045380; P:positive regulation of interleukin-17 biosynthetic process; ISS:ARUK-UCL.
DR   GO; GO:0032755; P:positive regulation of interleukin-6 production; IDA:BHF-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:1903800; P:positive regulation of production of miRNAs involved in gene silencing by miRNA; 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:0045893; P:positive regulation of transcription, DNA-templated; IDA:UniProtKB.
DR   GO; GO:0045727; P:positive regulation of translation; IDA:UniProtKB.
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:0043687; P:post-translational protein modification; TAS:Reactome.
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: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:0051384; P:response to glucocorticoid; IDA:BHF-UCL.
DR   GO; GO:0032494; P:response to peptidoglycan; NAS:BHF-UCL.
DR   GO; GO:0072540; P:T-helper 17 cell lineage commitment; ISS:UniProtKB.
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; PTHR10511; 1.
DR   PANTHER; PTHR10511:SF3; PTHR10511:SF3; 1.
DR   Pfam; PF00489; IL6; 1.
DR   PIRSF; PIRSF001935; IL6_MGF_GCSF; 1.
DR   PRINTS; PR00433; IL6GCSFMGF.
DR   SMART; SM00126; IL6; 1.
DR   SUPFAM; SSF47266; SSF47266; 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; Polymorphism;
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:0000244|PDB:1ALU"
FT   STRAND          76..79
FT                   /evidence="ECO:0000244|PDB:2IL6"
FT   TURN            81..83
FT                   /evidence="ECO:0000244|PDB:4CNI"
FT   HELIX           84..87
FT                   /evidence="ECO:0000244|PDB:4CNI"
FT   HELIX           97..99
FT                   /evidence="ECO:0000244|PDB:1ALU"
FT   STRAND          102..105
FT                   /evidence="ECO:0000244|PDB:4J4L"
FT   HELIX           108..132
FT                   /evidence="ECO:0000244|PDB:1ALU"
FT   STRAND          134..136
FT                   /evidence="ECO:0000244|PDB:4J4L"
FT   HELIX           137..157
FT                   /evidence="ECO:0000244|PDB:1ALU"
FT   STRAND          159..161
FT                   /evidence="ECO:0000244|PDB:1ALU"
FT   HELIX           169..180
FT                   /evidence="ECO:0000244|PDB:1ALU"
FT   HELIX           184..209
FT                   /evidence="ECO:0000244|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
//