Suppressors of Cytokine Signalling (SOCS) have Neuroprot

National Eye Institute

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Abstract

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 that is 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 proteins 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. Although the role of CIS, SOCS1, SOCS2 or SOCS3 in negative feedback regulation of cytokine and growth factor signaling is firmly established, functions of SOCS4, SOCS5, SOCS6 and SOCS7 are largely unknown. In this study, we have investigated the possibility that SOCS proteins are involved in mechanisms by which retinal cells are protected from oxidative stress-induced neuronal cell death, light-induced damage of photoreceptors and retinal degenerative effects of pro-inflammatory cytokines. We show for the first time that SOCS5, SOCS6, SOCS7 are constitutively expressed in the retina, while SOCS1, SOCS2, SOCS3 and CIS are undetectable but are induced by proinflammatory cytokines and growth factors. We further show that SOCS proteins are induced in the retina by high intensity light and following exposure of retinal cells to hypoxic conditions. Demonstration that retinal cells respond to cytotoxic cytokines, hypoxia or high intensity light by upregulating SOCS expression, suggest that SOCS proteins may mitigate injurious effects of environmental, chemical or oxidative stress in the eye and may therefore be a potentially important neuroprotective agents of the mammalian retina.