Cytokines are secreted proteins that regulate important cellular responses such as proliferation and differentiation. Key events in cytokine signal transduction are well defined: cytokines induce receptor aggregation, leading to activation of members of the JAK family of cytoplasmic tyrosine kinases. In turn, members of the STAT family of transcription factors are phosphorylated, dimerize and increase the transcription of genes with STAT recognition sites in their promoters. Less is known of how cytokine signal transduction is switched off. We have cloned a complementary DNA encoding a protein SOCS-1, containing an SH2-domain, by its ability to inhibit the macrophage differentiation of M1 cells in response to interleukin-6. Expression of SOCS-1 inhibited both interleukin-6-induced receptor phosphorylation and STAT activation. We have also cloned two relatives of SOCS-1, named SOCS-2 and SOCS-3, which together with the previously described CIS form a new family of proteins. Transcription of all four SOCS genes is increased rapidly in response to interleukin-6, in vitro and in vivo, suggesting they may act in a classic negative feedback loop to regulate cytokine signal transduction.

The interleukin-6 (IL-6) family of cytokines consists of oncostatin M (OSM), leukemia inhibitory factor (LIF), ciliary neurotrophic factor (CNTF), cardiotrophin-1 (CT-1), and cardiotrophin-like cytokine factor 1 (CLCF1). Membership of this cytokine family is defined by usage of common β-receptor signalling subunits, which activate various intracellular signalling pathways. Each IL-6 family member elicits responses essential to the physiological control of immune homeostasis, haematopoiesis, inflammation, development and metabolism. Accordingly, distortion of these cytokine activities often promotes chronic disease and cancer; the pathological significance of this is exemplified by the successful treatment of certain autoimmune conditions with drugs that target the IL-6 pathway. Here, we discuss the emerging roles for IL-6 family members in infection, chronic inflammation, autoimmunity and cancer, and review therapeutic strategies designed to manipulate these cytokines in disease. [H1] IntroductionCytokines contribute to all aspects of human biology and have evolved to enable the sensing and interpretation of environmental cues relevant to the maintenance of normal host physiology 1 . Although these secretory proteins are best known for their role as custodians of immune homeostasis and the inflammatory response to infection, trauma or injury, their diverse functions also affect embryonic development, cognitive function and behaviour, tissue integrity, and ageing. In this regard, cytokines often display pleiotropic or overlapping functional properties 1 .The interleukin-6 (IL-6) cytokine family comprises IL-6, IL-11, IL-27, IL-31, oncostatin M (OSM), leukemia inhibitory factor (LIF), ciliary neurotrophic factor (CNTF), cardiotrophin-1 (CT-1) and cardiotrophin-like cytokine factor 1 (CLCF1), and among all cytokine families it arguably displays the highest degree of functional pleiotropy and redundancy in eliciting responses relevant to health and disease 2 . Members of this family play prominent roles in chronic inflammation, autoimmunity, infectious disease and cancer (BOX 1), where they often act as diagnostic or prognostic indicators of disease activity and response to therapy 1,3-6 . Moreover, IL-6 family cytokines are now viewed as major therapeutic targets for clinical intervention [3][4][5][6][7][8][9] . This is epitomized by the treatment of chronic immune-related conditions, such as inflammatory arthritis, giant cell arteritis and Castleman's disease, with drugs that target IL-6 5,10-12 . In this Review, we will draw on recent advances to provide a timely update on the biology of IL-6 family cytokines and their clinical potential as therapeutic targets or disease modifiers in autoimmunity, inflammation, infection and cancer. [H1] What constitutes IL-6 family membership?IL-6 remains the archetypal member of the IL-6 cytokine family, and regulates a diverse array of functions relevant to haematopoiesis, tissue homeostasis, metabolism and immunity (BOX 1 &Jones & Jenkins, 2018 Nature Reviews ImmunologyThe ...

The intracellular signaling mechanisms that specify tissue-specific responses to the interleukin-6 (IL-6) family of cytokines are not well understood. Here, we evaluated the functions of the two major signaling pathways, the signal transducers and activators of transcription 1 and 3 (STAT1/3) and the Src-homology tyrosine phosphatase 2 (SHP2)-Ras-ERK, emanating from the common signal transducer, gp130, in the gastrointestinal tract. Gp130(757F) mice, with a 'knock-in' mutation abrogating SHP2-Ras-ERK signaling, developed gastric adenomas by three months of age. In contrast, mice harboring the reciprocal mutation ablating STAT1/3 signaling (gp130(Delta STAT)), or deficient in IL-6-mediated gp130 signaling (IL-6(-/-) mice), showed impaired colonic mucosal wound healing. These gastrointestinal phenotypes are highly similar to the phenotypes exhibited by mice deficient in trefoil factor 1 (pS2/TFF1) and intestinal trefoil factor (ITF)/TFF3, respectively, and corresponded closely with the capacity of the two pathways to stimulate transcription of the genes encoding pS2/TFF1 and ITF/TFF3. We propose a model whereby mucosal wound healing depends solely on activation of STAT1/3, whereas gastric hyperplasia ensues when the coordinated activation of the STAT1/3 and SHP2-Ras-ERK pathways is disrupted.