The IL (interleukin)-6-type cytokines IL-6, IL-11, LIF (leukaemia inhibitory factor), OSM (oncostatin M), ciliary neurotrophic factor, cardiotrophin-1 and cardiotrophin-like cytokine are an important family of mediators involved in the regulation of the acute-phase response to injury and infection. Besides their functions in inflammation and the immune response, these cytokines play also a crucial role in haematopoiesis, liver and neuronal regeneration, embryonal development and fertility. Dysregulation of IL-6-type cytokine signalling contributes to the onset and maintenance of several diseases, such as rheumatoid arthritis, inflammatory bowel disease, osteoporosis, multiple sclerosis and various types of cancer (e.g. multiple myeloma and prostate cancer). IL-6-type cytokines exert their action via the signal transducers gp (glycoprotein) 130, LIF receptor and OSM receptor leading to the activation of the JAK/STAT (Janus kinase/signal transducer and activator of transcription) and MAPK (mitogen-activated protein kinase) cascades. This review focuses on recent progress in the understanding of the molecular mechanisms of IL-6-type cytokine signal transduction. Emphasis is put on the termination and modulation of the JAK/STAT signalling pathway mediated by tyrosine phosphatases, the SOCS (suppressor of cytokine signalling) feedback inhibitors and PIAS (protein inhibitor of activated STAT) proteins. Also the cross-talk between the JAK/STAT pathway with other signalling cascades is discussed.
Abbreviations used: α2M, α2-macroglobulin; CBM, cytokine-binding module; CIS, cytokine-inducible SH2 protein; CLC, cardiotrophin-like cytokine; CLF, cytokine-like factor; CNTF, ciliary neurotrophic factor; CT, cardiotrophin; EGF, epidermal growth factor; Epo, erythropoietin; ERK, extracellular-regulated kinase; EZI, endothelial cell-derived zinc-finger protein; Fab, fragment antigen binding; FERM, four-point-one, ezrin, radixin, moesin; FKHR, forkhead-related transcription factor; FN, fibronectin; Gab, Grb-associated binder; gp, glycoprotein; Grb, growth-factor-receptor-bound protein; Hck, haematopoietic cell kinase; IFN, interferon; IL, interleukin; IRS, insulin receptor substrate; JAK, Janus kinase; JNK, c-Jun N-terminal kinase; KIR, kinase inhibitory region; KSHV, Kaposi's sarcoma-associated herpes virus; LIF, leukaemia inhibitory factor; LPS, lipopolysaccharide; MAPK, mitogen-activated protein kinase; MK2, MAPK-activated protein kinase 2; NES, nuclear export signal; NF-κB, nuclear factor κB; NLS, nuclear localization signal; Nmi, N-Myc-interactor; OSM, oncostatin M; p, phospho-; PDGF, platelet-derived growth factor; PH, pleckstrin homology; PKC, protein kinase C; PI3K, phosphoinositide 3-kinase; PIAS, protein inhibitor of activated STAT; PRMT, protein arginine methyltransferase; PTP, protein tyrosine phosphatase; R, receptor; s, soluble; SH2, Src homology 2; SHC, SH2 and collagen homology domain containing protein; SHP, SH2-domain-containing tyrosine phosphatase; SMRT, silencing mediator of retinoic and thyroid hormone receptors; SOCS, suppressor of cytokine signalling; SOS, Son of Sevenless; SSI, STAT-induced STAT inhibitor; STAT, signal transducer and activator of transcription; TNF, tumour necrosis factor.
All authors contributed equally to this review article.