Abstract
IL (interleukin)-6, which was originally identified as a B-cell differentiation factor, is a multifunctional cytokine that regulates the immune response, haemopoiesis, the acute phase response and inflammation. IL-6 is produced by various types of cell and influences various cell types, and has multiple biological activities through its unique receptor system. IL-6 exerts its biological activities through two molecules: IL-6R (IL-6 receptor) and gp130. When IL-6 binds to mIL-6R (membrane-bound form of IL-6R), homodimerization of gp130 is induced and a high-affinity functional receptor complex of IL-6, IL-6R and gp130 is formed. Interestingly, sIL-6R (soluble form of IL-6R) also binds with IL-6, and the IL-6–sIL-6R complex can then form a complex with gp130. The homodimerization of receptor complex activates JAKs (Janus kinases) that then phosphorylate tyrosine residues in the cytoplasmic domain of gp130. The gp130-mediated JAK activation by IL-6 triggers two main signalling pathways: the gp130 Tyr759-derived SHP-2 (Src homology 2 domain-containing protein tyrosine phosphatase-2)/ERK (extracellular-signal-regulated kinase) MAPK (mitogen-activated protein kinase) pathway and the gp130 YXXQ-mediated JAK/STAT (signal transducer and activator of transcription) pathway. Increased IL-6 levels are observed in several human inflammatory diseases, such as rheumatoid arthritis, Castleman's disease and systemic juvenile idiopathic arthritis. IL-6 is also critically involved in experimentally induced autoimmune diseases. All clinical findings and animal models suggest that IL-6 plays a number of critical roles in the pathogenesis of autoimmune diseases. In the present review, we first summarize the IL-6/IL-6R system and IL-6 signal transduction, and then go on to discuss the physiological and pathological roles of IL-6.
- autoimmune disease
- bone metabolism
- immune response
- inflammation
- interleukin-6 (IL-6) signalling
Abbreviations: AA, amyloid A; ACD, anaemia of chronic disease; ADAM, a disintegrin and metalloproteinase; ADAMTS, ADAM with thrombospondin motifs; α1-AGP, α1-acid glycoprotein; AMD, age-related macular degeneration; APP, acute-phase protein; APR, acute-phase response; AR, androgen receptor; BSF, B-cell stimulatory factor; CAC, colitis-associated cancer; CCL, CC chemokine ligand; CD62L, CD62 ligand; CNV, choroidal neovascularization; CRP, C-reactive protein; ERK, extracellular-signal-regulated kinase; FAS, fatty acid synthase; GM-CSF, granulocyte/macrophage colony-stimulating factor; HDL, high-density lipoprotein; ICAM, intercellular adhesion molecule; IFN, interferon; IGF-1, insulin-like growth factor-1; IL, interleukin; IL-6R, IL-6 receptor; JAK, Janus kinase; JIA, juvenile idiopathic arthritis; LPS, lipopolysaccharide; MAPK, mitogen-activated protein kinase; MCP, monocyte chemoattractant protein; mgp130, membrane-bound gp130; mIL-6R, membrane-bound IL-6R; MM, multiple myeloma; MMP, matrix metalloproteinase; PBEF, pre-B-cell colony-enhancing factor; PPAR, peroxisome-proliferator-activated receptor; RA, rheumatoid arthritis; RA-FLS, fibroblast-like synoviocytes from RA patients; RANKL, receptor activator of nuclear factor κB ligand; ROR, retinoic acid-receptor-related orphan receptor; SAA, serum AA; sgp130, soluble gp130; SHP-2, Src homology domain-containing protein tyrosine phosphatase-2; sIL-6R, soluble IL-6R; sJIA, systemic JIA; SOCS, suppressor of cytokine signalling; SREBP, sterol-regulatory-element-binding protein; STAT, signal transducer and activator of transcription; TAG, triacylglycerol; TCZ, tocilizumab; TGF, transforming growth factor; TNF, tumour necrosis factor; Treg, regulatory T-cell; VEGF, vascular endothelial growth factor; VLDL, very-low-density lipoprotein
- © The Authors Journal compilation © 2012 Biochemical Society
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February 2012
Volume: 122 Issue: 4
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