Suppressor of cytokine signaling (SOCS) family of proteins contain eight members (SOCS1 through SOCS7;and cytokine-induced SH2-containing protein or CIS), each of which contains a conserved central Src homology 2 (SH2) domain flanked by a variable length N-terminal domain and a 40-amino acid C-terminal domain called the SOCS box. SOCS proteins regulate signals transmitted by hemopoietin cytokine receptors with associated JAK kinases. Signals induced by insulin and growth factors whose receptors possess intrinsic tyrosine kinase activity (IGF-1, FGFs, PDGF, EGF and erythropoietin) are also under feedback regulation by SOCS proteins. Significant interest in SOCS family stems from the belief that SOCS proteins function to integrate multiple cytokine/growth factor signals and mediate cross-communication between antagonistic factors. Importance of SOCS proteins is underscored by the wide array of pathologic conditions that result from deletion of SOCS genes or dysregulation of SOCS genes expression. These include allergic and autoimmune diseases, insulin resistance, diabetes, liver degeneration, lymphoid deficiencies, polycystic kidney disease and cancer. In this study, our focus has been in two areas: (i) Potential neuroprotective roles of SOCS proteins. We examined the temporal expression of inflammatory cytokines and SOCS genes in the retina, blood and lymph nodes from mice with experimental autoimmune uveitis (EAU), a T cell-mediated disease that serves as model of human uveitis to determine whether the pattern of SOCS expression correlates with severity of EAU or host protective mechanisms. We found that SOCS1 and SOCS3 proteins that are induced by inflammatory cytokines play important roles in mitigating uveitis by negative regulation of IFNg activity during EAU while SOCS5 that is constitutively expressed in the retina exerts a protective function. These results suggest that SOCS proteins may function to curtail the duration of deleterious activities of pro-inflammatory cytokines in the retina and augment levels of trophic factors that enhance survival of injured retinal cells. (ii) Potential role of SOCS proteins in insulin-resistance and diabetic retinopathy. Our studies reveal that although SOCS1, SOCS3 or CIS mRNAs or proteins are barely detectable in the retina, their expression is markedly induced during inflammation. In addition, IFNg produced by inflammatory cells synergizes with insulin to further enhance SOCS1 and SOCS3 expression in retina and induces the inhibition of AKT (PKB) activation by insulin in the retina. In contrast to the cytokine-inducible SOCS (SOCS1, SOCS3, CIS), we found that SOCS5, SOCS6 and SOCS7 proteins are constitutively expressed in the retina and the depletion of endogenous SOCS6 levels in retinal cells induces inhibition of insulin-induced AKT activation. These results suggest that inflammatory molecules such as IFNg may promote insulin resistance in the retina by inducing expression of CIS, SOCS1 or SOCS3 while constitutive SOCS proteins such as SOCS6 may promote insulin signaling in retina and may have neuroprotective functions.
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