ID IL6_RAT Reviewed; 211 AA. AC P20607; DT 01-FEB-1991, integrated into UniProtKB/Swiss-Prot. DT 01-FEB-1991, sequence version 1. DT 27-MAR-2024, entry version 175. DE RecName: Full=Interleukin-6 {ECO:0000305}; DE Short=IL-6; DE Flags: Precursor; GN Name=Il6 {ECO:0000312|RGD:2901}; Synonyms=Il-6; OS Rattus norvegicus (Rat). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; OC Murinae; Rattus. OX NCBI_TaxID=10116; RN [1] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA]. RX PubMed=2789217; DOI=10.1016/s0021-9258(18)71589-5; RA Northemann W., Braciak T.A., Hattori M., Lee F., Fey G.H.; RT "Structure of the rat interleukin 6 gene and its expression in macrophage- RT derived cells."; RL J. Biol. Chem. 264:16072-16082(1989). RN [2] RP SUBCELLULAR LOCATION, AND INDUCTION BY ENDOCANNABINOID ANANDAMIDE AND IL1B. RX PubMed=23955712; DOI=10.1038/nm.3265; RA Jourdan T., Godlewski G., Cinar R., Bertola A., Szanda G., Liu J., Tam J., RA Han T., Mukhopadhyay B., Skarulis M.C., Ju C., Aouadi M., Czech M.P., RA Kunos G.; RT "Activation of the Nlrp3 inflammasome in infiltrating macrophages by RT endocannabinoids mediates beta cell loss in type 2 diabetes."; RL Nat. Med. 19:1132-1140(2013). 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:P08505}. 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. In the adaptive immune response, is required for the CC differentiation of B-cells into immunoglolin-secreting cells. Plays a CC major role in the differentiation of CD4(+) T cell subsets. Essential CC factor for the development of T follicular helper (Tfh) cells that are CC required for the induction of germinal-center formation. Together with CC IL21, controls the early generation of Tfh cells and are critical for CC an effective antibody response to acute viral infection. Required to CC drive naive CD4(+) T cells to the Th17 lineage, through 'cluster CC signaling' by dendritic cells. Also required for proliferation of CC myeloma cells and the survival of plasmablast cells. CC {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. 'Trans-signaling' in central nervous CC system regulates energy and glucose homeostasis. Mediates, through GLP- CC 1, crosstalk between insulin-sensitive tissues, intestinal L cells and CC pancreatic islets to adapt to changes in insulin demand (By CC similarity). Also acts as a myokine (By similarity). Plays a protective CC role during liver injury, being required for maintenance of tissue CC regeneration. Also has a pivotal role in iron metabolism by regulating CC HAMP/hepcidin expression upon inflammation or bacterial infection. CC Through activation of IL6ST-YAP-NOTCH pathway, induces inflammation- CC induced epithelial regeneration (By similarity). CC {ECO:0000250|UniProtKB:P05231, 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:P08505}. CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:23955712}. CC -!- INDUCTION: In pancreatic islets, secretion is stimulated by IL1B. In CC islets from Zucker diabetic fatty (ZDF) rats, but not lean animals, CC secretion is also increased by endocannabinoid anandamide/AEA. CC {ECO:0000269|PubMed:23955712}. CC -!- SIMILARITY: Belongs to the IL-6 superfamily. {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; M26744; AAA77659.1; -; mRNA. DR EMBL; M26745; AAA41430.1; -; Genomic_DNA. DR PIR; A34247; A34247. DR RefSeq; NP_036721.1; NM_012589.2. DR AlphaFoldDB; P20607; -. DR SMR; P20607; -. DR STRING; 10116.ENSRNOP00000013732; -. DR PhosphoSitePlus; P20607; -. DR PaxDb; 10116-ENSRNOP00000013732; -. DR Ensembl; ENSRNOT00000013732.7; ENSRNOP00000013732.6; ENSRNOG00000010278.7. DR Ensembl; ENSRNOT00055008887; ENSRNOP00055006755; ENSRNOG00055005535. DR Ensembl; ENSRNOT00060041923; ENSRNOP00060034766; ENSRNOG00060024169. DR Ensembl; ENSRNOT00065006164; ENSRNOP00065004398; ENSRNOG00065004225. DR GeneID; 24498; -. DR KEGG; rno:24498; -. DR UCSC; RGD:2901; rat. DR AGR; RGD:2901; -. DR CTD; 3569; -. DR RGD; 2901; Il6. DR eggNOG; ENOG502S7Q4; Eukaryota. DR GeneTree; ENSGT00390000000878; -. DR HOGENOM; CLU_096521_0_0_1; -. DR InParanoid; P20607; -. DR OMA; FSKCENS; -. DR OrthoDB; 5352039at2759; -. DR PhylomeDB; P20607; -. DR Reactome; R-RNO-1059683; Interleukin-6 signaling. DR Reactome; R-RNO-110056; MAPK3 (ERK1) activation. DR Reactome; R-RNO-112411; MAPK1 (ERK2) activation. DR Reactome; R-RNO-381426; Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs). DR Reactome; R-RNO-8957275; Post-translational protein phosphorylation. DR PRO; PR:P20607; -. DR Proteomes; UP000002494; Chromosome 4. DR Bgee; ENSRNOG00000010278; Expressed in spleen and 5 other cell types or tissues. DR GO; GO:0009897; C:external side of plasma membrane; ISO:RGD. DR GO; GO:0005615; C:extracellular space; IDA:RGD. DR GO; GO:0005896; C:interleukin-6 receptor complex; ISS:UniProtKB. DR GO; GO:0005125; F:cytokine activity; IDA:RGD. DR GO; GO:0008083; F:growth factor activity; ISO:RGD. DR GO; GO:0005138; F:interleukin-6 receptor binding; IDA:RGD. DR GO; GO:0005102; F:signaling receptor binding; IDA:RGD. DR GO; GO:0006953; P:acute-phase response; IEA:UniProtKB-KW. DR GO; GO:0046849; P:bone remodeling; IEP:RGD. DR GO; GO:0060445; P:branching involved in salivary gland morphogenesis; ISO:RGD. DR GO; GO:0045454; P:cell redox homeostasis; IMP:RGD. DR GO; GO:0071345; P:cellular response to cytokine stimulus; IEP:RGD. DR GO; GO:0071549; P:cellular response to dexamethasone stimulus; IEP:RGD. DR GO; GO:0071392; P:cellular response to estradiol stimulus; IEP:RGD. DR GO; GO:0035729; P:cellular response to hepatocyte growth factor stimulus; ISO:RGD. DR GO; GO:0070301; P:cellular response to hydrogen peroxide; IEP:RGD. DR GO; GO:0071347; P:cellular response to interleukin-1; IEP:RGD. DR GO; GO:0097398; P:cellular response to interleukin-17; ISO:RGD. DR GO; GO:0071222; P:cellular response to lipopolysaccharide; IEP:RGD. DR GO; GO:0031669; P:cellular response to nutrient levels; IEP:RGD. DR GO; GO:1990646; P:cellular response to prolactin; IEP:RGD. DR GO; GO:0071356; P:cellular response to tumor necrosis factor; IEP:RGD. DR GO; GO:0098586; P:cellular response to virus; ISS:UniProtKB. DR GO; GO:0019221; P:cytokine-mediated signaling pathway; ISO:RGD. DR GO; GO:0042832; P:defense response to protozoan; ISO:RGD. DR GO; GO:0051607; P:defense response to virus; ISO:RGD. DR GO; GO:0031018; P:endocrine pancreas development; ISO:RGD. DR GO; GO:0060664; P:epithelial cell proliferation involved in salivary gland morphogenesis; ISO:RGD. DR GO; GO:0010467; P:gene expression; ISO:RGD. DR GO; GO:0002314; P:germinal center B cell differentiation; ISS:UniProtKB. DR GO; GO:0070091; P:glucagon secretion; ISO:RGD. DR GO; GO:0042593; P:glucose homeostasis; ISS:UniProtKB. DR GO; GO:0002384; P:hepatic immune response; ISO:RGD. DR GO; GO:0072574; P:hepatocyte proliferation; ISS:UniProtKB. DR GO; GO:0006954; P:inflammatory response; ISO:RGD. DR GO; GO:0090594; P:inflammatory response to wounding; ISO:RGD. DR GO; GO:0070102; P:interleukin-6-mediated signaling pathway; ISS:UniProtKB. DR GO; GO:0097421; P:liver regeneration; ISS:UniProtKB. DR GO; GO:0031294; P:lymphocyte costimulation; IEP:RGD. DR GO; GO:0046716; P:muscle cell cellular homeostasis; ISO:RGD. DR GO; GO:0002262; P:myeloid cell homeostasis; ISO:RGD. DR GO; GO:0043066; P:negative regulation of apoptotic process; ISO:RGD. DR GO; GO:0045779; P:negative regulation of bone resorption; ISO:RGD. DR GO; GO:0008285; P:negative regulation of cell population proliferation; IMP:RGD. DR GO; GO:0032682; P:negative regulation of chemokine production; ISO:RGD. DR GO; GO:0032966; P:negative regulation of collagen biosynthetic process; ISO:RGD. DR GO; GO:0045721; P:negative regulation of gluconeogenesis; IDA:RGD. DR GO; GO:0046888; P:negative regulation of hormone secretion; ISO:RGD. DR GO; GO:2000660; P:negative regulation of interleukin-1-mediated signaling pathway; ISO:RGD. DR GO; GO:0045837; P:negative regulation of membrane potential; IMP:RGD. DR GO; GO:0048635; P:negative regulation of muscle organ development; IDA:RGD. DR GO; GO:0043524; P:negative regulation of neuron apoptotic process; IDA:RGD. DR GO; GO:2000635; P:negative regulation of primary miRNA processing; ISO:RGD. DR GO; GO:0031175; P:neuron projection development; ISO:RGD. DR GO; GO:0001781; P:neutrophil apoptotic process; ISO:RGD. DR GO; GO:0002675; P:positive regulation of acute inflammatory response; ISO:RGD. DR GO; GO:1902512; P:positive regulation of apoptotic DNA fragmentation; ISO:RGD. DR GO; GO:0043065; P:positive regulation of apoptotic process; ISO:RGD. DR GO; GO:0050871; P:positive regulation of B cell activation; ISO:RGD. DR GO; GO:0008284; P:positive regulation of cell population proliferation; ISO:RGD. DR GO; GO:0071864; P:positive regulation of cell proliferation in bone marrow; ISO:RGD. DR GO; GO:0032722; P:positive regulation of chemokine production; ISO:RGD. DR GO; GO:1900017; P:positive regulation of cytokine production involved in inflammatory response; ISO:RGD. DR GO; GO:0045740; P:positive regulation of DNA replication; IMP:RGD. DR GO; GO:0045893; P:positive regulation of DNA-templated transcription; ISO:RGD. DR GO; GO:0050679; P:positive regulation of epithelial cell proliferation; ISO:RGD. DR GO; GO:0010718; P:positive regulation of epithelial to mesenchymal transition; ISO:RGD. DR GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; IDA:RGD. DR GO; GO:0090091; P:positive regulation of extracellular matrix disassembly; ISO:RGD. DR GO; GO:0010628; P:positive regulation of gene expression; IDA:ARUK-UCL. DR GO; GO:0060252; P:positive regulation of glial cell proliferation; ISO:RGD. DR GO; GO:0014015; P:positive regulation of gliogenesis; ISO:RGD. DR GO; GO:0002639; P:positive regulation of immunoglobulin production; ISS:UniProtKB. DR GO; GO:0032731; P:positive regulation of interleukin-1 beta production; ISO:RGD. DR GO; GO:0032733; P:positive regulation of interleukin-10 production; ISO:RGD. DR GO; GO:0032740; P:positive regulation of interleukin-17 production; ISO:RGD. DR GO; GO:0032745; P:positive regulation of interleukin-21 production; ISS:UniProtKB. DR GO; GO:0032755; P:positive regulation of interleukin-6 production; ISO:RGD. DR GO; GO:0032757; P:positive regulation of interleukin-8 production; ISO:RGD. DR GO; GO:1904996; P:positive regulation of leukocyte adhesion to vascular endothelial cell; ISO:RGD. DR GO; GO:0043410; P:positive regulation of MAPK cascade; ISO:RGD. DR GO; GO:0045666; P:positive regulation of neuron differentiation; IMP:RGD. DR GO; GO:0010976; P:positive regulation of neuron projection development; IMP:RGD. DR GO; GO:0045429; P:positive regulation of nitric oxide biosynthetic process; IDA:RGD. DR GO; GO:0045669; P:positive regulation of osteoblast differentiation; ISO:RGD. DR GO; GO:0033138; P:positive regulation of peptidyl-serine phosphorylation; ISO:RGD. DR GO; GO:0050731; P:positive regulation of peptidyl-tyrosine phosphorylation; ISO:RGD. DR GO; GO:0051897; P:positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction; IDA:RGD. DR GO; GO:1901731; P:positive regulation of platelet aggregation; ISO:RGD. DR GO; GO:0042307; P:positive regulation of protein import into nucleus; IDA:RGD. DR GO; GO:0046427; P:positive regulation of receptor signaling pathway via JAK-STAT; IDA:RGD. DR GO; GO:1904894; P:positive regulation of receptor signaling pathway via STAT; ISO:RGD. DR GO; GO:0048661; P:positive regulation of smooth muscle cell proliferation; ISO:RGD. DR GO; GO:0042102; P:positive regulation of T cell proliferation; ISO:RGD. DR GO; GO:2000553; P:positive regulation of T-helper 2 cell cytokine production; ISO:RGD. DR GO; GO:0045630; P:positive regulation of T-helper 2 cell differentiation; ISO:RGD. DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; ISO:RGD. DR GO; GO:0045727; P:positive regulation of translation; ISO:RGD. DR GO; GO:0051971; P:positive regulation of transmission of nerve impulse; IDA:RGD. DR GO; GO:0032760; P:positive regulation of tumor necrosis factor production; ISO:RGD. DR GO; GO:0042531; P:positive regulation of tyrosine phosphorylation of STAT protein; ISO:RGD. DR GO; GO:0010575; P:positive regulation of vascular endothelial growth factor production; ISO:RGD. DR GO; GO:0042981; P:regulation of apoptotic process; ISO:RGD. DR GO; GO:0042127; P:regulation of cell population proliferation; ISO:RGD. DR GO; GO:0008360; P:regulation of cell shape; IDA:RGD. DR GO; GO:0045188; P:regulation of circadian sleep/wake cycle, non-REM sleep; IMP:RGD. 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:0010574; P:regulation of vascular endothelial growth factor production; ISO:RGD. DR GO; GO:0014823; P:response to activity; ISS:UniProtKB. DR GO; GO:0043200; P:response to amino acid; IEP:RGD. DR GO; GO:0010996; P:response to auditory stimulus; IEP:RGD. DR GO; GO:0009617; P:response to bacterium; IEP:RGD. DR GO; GO:0031000; P:response to caffeine; IEP:RGD. DR GO; GO:0051592; P:response to calcium ion; IEP:RGD. DR GO; GO:0034097; P:response to cytokine; IEP:RGD. DR GO; GO:0051602; P:response to electrical stimulus; IEP:RGD. DR GO; GO:0051384; P:response to glucocorticoid; ISO:RGD. DR GO; GO:0140459; P:response to Gram-positive bacterium; IEP:RGD. DR GO; GO:0032868; P:response to insulin; IEP:RGD. DR GO; GO:0032496; P:response to lipopolysaccharide; IEP:RGD. DR GO; GO:0009612; P:response to mechanical stimulus; IEP:RGD. DR GO; GO:0031667; P:response to nutrient levels; IEP:RGD. DR GO; GO:0014070; P:response to organic cyclic compound; IEP:RGD. DR GO; GO:0009611; P:response to wounding; ISO:RGD. DR GO; GO:0009410; P:response to xenobiotic stimulus; IEP:RGD. DR GO; GO:0001878; P:response to yeast; IEP:RGD. DR GO; GO:0042110; P:T cell activation; ISO:RGD. 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:0045064; P:T-helper 2 cell differentiation; ISO:RGD. 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-like. DR InterPro; IPR030474; IL-6/GCSF/MGF. DR InterPro; IPR030473; IL6/GCSF/MGF_CS. DR PANTHER; PTHR48406; INTERLEUKIN-6; 1. DR PANTHER; PTHR48406:SF1; 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. DR Genevisible; P20607; RN. PE 2: Evidence at transcript level; KW Acute phase; Cytokine; Disulfide bond; Growth factor; Phosphoprotein; KW Reference proteome; Secreted; Signal. FT SIGNAL 1..24 FT /evidence="ECO:0000255" FT CHAIN 25..211 FT /note="Interleukin-6" FT /id="PRO_0000015593" FT MOD_RES 79 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:P05231" FT DISULFID 70..76 FT /evidence="ECO:0000250|UniProtKB:P05231" FT DISULFID 99..109 FT /evidence="ECO:0000250|UniProtKB:P05231" SQ SEQUENCE 211 AA; 24357 MW; 17D248A14F96B5C1 CRC64; MKFLSARDFQ PVAFLGLMLL TATAFPTSQV RRGDFTEDTT HNRPVYTTSQ VGGLITYVLR EILEMRKELC NGNSDCMNSD DALSENNLKL PEIQRNDGCF QTGYNQEICL LKICSGLLEF RFYLEFVKNN LQDNKKDKAR VIQSNTETLV HIFKQEIKDS YKIVLPTPTS NALLMEKLES QKEWLRTKTI QLILKALEEF LKVTMRSTRQ T //