ID   IL6_NEOVI               Reviewed;         125 AA.
AC   P41693;
DT   01-NOV-1995, integrated into UniProtKB/Swiss-Prot.
DT   01-NOV-1995, sequence version 1.
DT   03-AUG-2022, entry version 90.
DE   RecName: Full=Interleukin-6;
DE            Short=IL-6;
DE   Flags: Fragment;
GN   Name=IL6;
OS   Neovison vison (American mink) (Mustela vison).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Laurasiatheria; Carnivora; Caniformia; Mustelidae; Mustelinae;
OC   Neogale.
OX   NCBI_TaxID=452646;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RA   Kanno H., Bloom M.E., Perryman S.M., Wolfinbarger J.B.;
RT   "Antibody-dependent infection by Aleutian mink disease parvovirus
RT   stimulates interleukin-6 production: possible role in the pathogenesis of
RT   an immune complex disease.";
RL   Submitted (JUL-1994) to the EMBL/GenBank/DDBJ databases.
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. The interaction with the membrane-
CC       bound IL6R and IL6ST stimulates 'classic signaling', whereas the
CC       binding of IL6 and soluble IL6R to IL6ST stimulates 'trans-signaling'.
CC       Alternatively, 'cluster signaling' occurs when membrane-bound IL6:IL6R
CC       complexes on transmitter cells activate IL6ST receptors on neighboring
CC       receiver cells. {ECO:0000250|UniProtKB:P05231}.
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 (By similarity). 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:P05231, ECO:0000250|UniProtKB:P08505}.
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. Induces,
CC       through 'trans-signaling' and synergistically with IL1B and TNF, the
CC       production of VEGF. Involved in metabolic controls, is discharged into
CC       the bloodstream after muscle contraction increasing lipolysis and
CC       improving insulin resistance (By similarity). 'Trans-signaling' in
CC       central nervous system also regulates energy and glucose homeostasis.
CC       Mediates, through GLP-1, crosstalk between insulin-sensitive tissues,
CC       intestinal L cells and pancreatic islets to adapt to changes in insulin
CC       demand (By similarity). Also acts as a myokine (By similarity). Plays a
CC       protective role during liver injury, being required for maintenance of
CC       tissue regeneration (By similarity). Also has a pivotal role in iron
CC       metabolism by regulating HAMP/hepcidin expression upon inflammation or
CC       bacterial infection (By similarity). Through activation of IL6ST-YAP-
CC       NOTCH pathway, induces inflammation-induced epithelial regeneration (By
CC       similarity). {ECO:0000250|UniProtKB:P05231,
CC       ECO:0000250|UniProtKB:P08505}.
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. Interacts with IL6R (via the N-terminal ectodomain); this
CC       interaction may be affected by IL6R-binding with SORL1, hence
CC       decreasing IL6 cis signaling. Interacts with SORL1 (via the N-terminal
CC       ectodomain); this interaction leads to IL6 internalization and
CC       lysosomal degradation. May form a trimeric complex with the soluble
CC       SORL1 ectodomain and soluble IL6R receptor; this interaction might
CC       stabilize circulating IL6, hence promoting IL6 trans signaling.
CC       {ECO:0000250|UniProtKB:P05231}.
CC   -!- SUBCELLULAR LOCATION: Secreted {ECO:0000250|UniProtKB:P05231}.
CC   -!- SIMILARITY: Belongs to the IL-6 superfamily. {ECO:0000305}.
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DR   EMBL; L34165; AAA96829.1; -; mRNA.
DR   AlphaFoldDB; P41693; -.
DR   SMR; P41693; -.
DR   PRIDE; P41693; -.
DR   Proteomes; UP000694425; Unplaced.
DR   GO; GO:0005615; C:extracellular space; IEA:UniProtKB-KW.
DR   GO; GO:0005125; F:cytokine activity; IEA:UniProtKB-KW.
DR   GO; GO:0008083; F:growth factor activity; IEA:UniProtKB-KW.
DR   GO; GO:0005138; F:interleukin-6 receptor binding; IEA:InterPro.
DR   GO; GO:0006953; P:acute-phase response; IEA:UniProtKB-KW.
DR   GO; GO:0042593; P:glucose homeostasis; ISS:UniProtKB.
DR   GO; GO:0072574; P:hepatocyte proliferation; ISS:UniProtKB.
DR   GO; GO:0070102; P:interleukin-6-mediated signaling pathway; ISS:UniProtKB.
DR   GO; GO:0097421; P:liver regeneration; ISS:UniProtKB.
DR   GO; GO:1904894; P:positive regulation of receptor signaling pathway via STAT; ISS:UniProtKB.
DR   GO; GO:0070092; P:regulation of glucagon secretion; ISS:UniProtKB.
DR   GO; GO:0050796; P:regulation of insulin secretion; ISS:UniProtKB.
DR   GO; GO:0014823; P:response to activity; 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; ISS:UniProtKB.
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; PTHR10511; 1.
DR   PANTHER; PTHR10511:SF3; PTHR10511:SF3; 1.
DR   Pfam; PF00489; IL6; 1.
DR   PRINTS; PR00433; IL6GCSFMGF.
DR   SMART; SM00126; IL6; 1.
DR   SUPFAM; SSF47266; SSF47266; 1.
DR   PROSITE; PS00254; INTERLEUKIN_6; 1.
PE   2: Evidence at transcript level;
KW   Acute phase; Cytokine; Disulfide bond; Growth factor; Reference proteome;
KW   Secreted.
FT   CHAIN           <1..125
FT                   /note="Interleukin-6"
FT                   /id="PRO_0000058761"
FT   DISULFID        16..26
FT                   /evidence="ECO:0000250"
FT   NON_TER         1
SQ   SEQUENCE   125 AA;  14604 MW;  8262DD35A998966A CRC64;
     AENNLKLPKL AEKDKCFQSQ FNQETCMTRI TTGLQEFQIH LKYLEANYEG NKNNAHSVYI
     STKHLLQKLR PMNQVEVTTP NPTTDSSLQA LFKSQDKWLK HVTIHLILRS LEDFLQFSLR
     AIRIM