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 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 regulate activities of pro-inflammatory cytokines in retinal cells and are involved in pathogenic mechanisms of insulin-resistance in the retina. Our studies reveal that expression of SOCS1, SOCS3 or CIS is low but detectable by the sensitive real-time RT-PCR assays. However, expression of these SOCS members is markedly induced by IFNg. IFNg synergizes with insulin to further enhance SOCS1 and SOCS3 expression in retina and we show that the augmentation of SOCS1 and SOCS3 expression induces the inhibition of AKT (PKB) activation by insulin in the retina. This observation is confirmed by our observation that forced over-expression of SOCS1 or SOCS3 in retinal cells inhibits AKT phosphorylation. In contrast to the cytokine-inducible SOCS (SOCS1, SOCS3, CIS), our Western blot and RPA analyses of human, rat, mouse retina and human cell lines reveal that SOCS5, SOCS6 and SOCS7 proteins are constitutively expressed in the retina. In addition, we have localized the expression of these SOCS members to ganglion-cell and photoreceptor-cell layers of the mouse retina by immunohistochemical analysis. Interestingly, siRNA-mediated depletion of retinal-cell endogenous SOCS6 levels induces significant 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 SOCS6 promotes insulin signaling in retina and may have neuroprotective functions.
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| Egwuagu, Charles E; Yu, Cheng-Hong; Mahdi, Rashid M et al. (2006) Cytokine-induced retinal degeneration: role of suppressors of cytokine signaling (SOCS) proteins in protection of the neuroretina. Adv Exp Med Biol 572:275-81 |
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| Egwuagu, Charles E; Yu, Cheng-Rong; Li, Zhuqing et al. (2005) SOCS5 mRNA levels in peripheral blood mononuclear cells (PBMC): a potential bio-marker for monitoring response of uveitis patients to Daclizumab therapy. J Autoimmun 24:39-46 |
