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X. Liu, Y. Lee, J. Tsai, R. Fariss, C. Yu, C.E. Egwuagu; Involvement of Distinct SOCS Family Members in Insulin Resistance and Protection of Neuroretina . Invest. Ophthalmol. Vis. Sci. 2006;47(13):4229.
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© ARVO (1962-2015); The Authors (2016-present)
Diabetic retinopathy is one of several ocular complications of diabetes. It is a leading cause of vision loss in developed countries and insulin resistance is implicated in etiology of diabetic retinopathy. Suppressor of cytokine signaling (SOCS) proteins inhibit insulin signals by targeting insulin receptor substrate (IRS) proteins and have recently been shown to induce insulin resistance in hepatic cells. Here, we have assessed the role of SOCS in normal retina, as well as, in retinal cells exposed to inflammatory cytokines.
SOCS expression in human or rodent retina was analyzed by RT–PCR or Western blotting and SOCS proteins were localized in mouse retina by immunohistochemical analysis. Functional consequences of SOCS over–expression in retina was determined by transfection of human RPE or Mueller cells with SOCS1 or SOCS3 expression plasmids while effects of SOCS6 depletion in insulin–stimulated retinal cells was assessed by RNA interference assay. SOCS and insulin target genes were analyzed by RPA, EMSA, Western blotting or Real–time RT–PCR.
We show that SOCS5, SOCS6, and SOCS7 proteins are constitutively expressed in the retina and we have localized expression of these SOCS members to the ganglion cell and photoreceptor cell layers of mouse retina by immunohistochemical analysis. In contrast, SOCS1, SOCS3 or CIS expression is low in the retina but rapidly inducible during inflammation by inflammatory mediators such as IFN–γ and IL–4. Of particular interest is our finding that IFN–γ synergizes with insulin to enhance expression of SOCS1 and SOCS3, resulting in the inhibition of AKT activation in the retina by insulin. Forced over–expression of SOCS1 or SOCS3 in retinal cells is shown to inhibit AKT phosphorylation while siRNA–mediated depletion of SOCS6 inhibits insulin–induced AKT activation, underscoring divergent functions of distinct SOCS proteins in the retina.
We provide evidence that SOCS proteins are constitutively and inducibly expressed in the retina. Our results showing that IFNγ synergizes with insulin to enhance SOCS expression and inhibit insulin signals in retinal cells, suggest that proinflammatory cytokines produced during inflammation may promote insulin resistance in the retina and contribute to devastating effects associated with ocular manifestation of diabetes. On the other hand, SOCS proteins that are constitutively expressed in the retina such as SOCS6 promote insulin signaling and may have protective functions in the neural retina.
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