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X. Liu, M. Mameza, H. Takase, J.Y. Tsai, C.R. Yu, C.E. Egwuagu; Interferon Gamma (IFN–) Induces Insulin Resistance in Retinal Organ Cultures by Upregulating Expression of Suppressor of Cytokine Signaling (SOCS) Protein . Invest. Ophthalmol. Vis. Sci. 2005;46(13):3112.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: Diabetic retinopathy is one of several ocular complications of diabetes and is a leading cause of vision loss in developed countries. Dysregulation of insulin signaling is a major factor in retinal and choroidal neovasculaization and derive in part from upregulated expression of various vascular mediators. SOCS proteins have recently been shown to modulate insulin signaling by targeting degradation of insulin receptor substrate–1 (IRS–1) and IRS–2. Inflammatory cytokines are potent inducers of SOCS expression. In this study we examined the possibility that inflammation and inflammatory mediators interfere with insulin signaling in the retina and may contribute to devastating effects associated with ocular manifestation of diabetes. Methods: Rat retina organ cultures or human retinal cell lines (ARPE or Muller cells) were stimulated with insulin alone or in the presence inflammatory cytokines (IFN–γ, IL–4) or proteins associated with bacterial (lipopolysaccharide) or viral (Poly I.C.) infection. Expression of SOCS (CIS, SOCS1, SOCS3, SOCS5, SOCS6, SOCS7), STATs (pSTAT1 & pSTAT3) or protein marker of insulin activation, pAKT, was analyzed by Western blotting, Real–time PCR or ribonuclease protection assay (RPA). Results:We show that SOCS5, SOCS6, and SOCS7 proteins are constitutively expressed in the retina while SOCS1, SOCS3 and CIS are inducible by inflammatory mediators, particularly IFN–γ and IL–4. In addition, IFN–γ is also found to synergize with insulin in inducing high levels of SOCS1 expression in retina and this correlates with inhibition of AKT activation by insulin. Conclusions: We provide evidence that SOCS proteins are constitutively expressed in the retina and that retinal cells respond to insulin stimulation by upregulating SOCS expression. Demonstration that the proinflammatory cytokine, IFN–γ, synergizes with insulin to enhance SOCS expression in retina and induce resistance of retinal cells to insulin, suggest that inflammatory molecules produced by inflammation may promote insulin resistance in the retina and contribute to devastating effects associated with ocular manifestation of diabetes.
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