Suppressors of Cytokine-Signaling Proteins Induce Insulin Resistance in the Retina and Promote Survival of Retinal Cells

Abstract

OBJECTIVE-Suppressors of cytokine signaling (SOCS) are implicated in the etiology of diabetes, obesity, and metabolic syndrome. Here, we show that some SOCS members are induced, while others are constitutively expressed, in retina and examine whether persistent elevation of SOCS levels in retina by chronic inflammation or cellular stress predisposes to developing insulin resistance in retina, a condition implicated in diabetic retinopathy.RESEARCH DESIGN AND METHODS-SOCS-mediated insulin resistance and neuroprotection in retina were investigated in 1) an experimental uveitis model, 2) SOCS1 transgenic rats, 3) insulin-deficient diabetic rats, 4) retinal cells depleted of SOCS6 or overexpressing SOCS1/SOCS3, and 5) oxidative stress and light-induced retinal degeneration models. RESULTS-Weshow that constitutive expression of SOCS6 protein in retinal neurons may improve glucose metabolism, while elevated SOCS1/SOCS3 expression during uveitis induces insulin resistance in neuroretina. SOCS-mediated insulin resistance, as indicated by its inhibition of basally active phosphoinositide 3-kinase/AKT signaling in retina, is validated in retinaspecific SOCS1 transgenic rats and retinal cells overexpressing SOCS1/SOCS3. We further show that the SOCS3 level is elevated in retina by oxidative stress, metabolic stress of insulin-deficient diabetes, or light-induced retinal damage and protects ganglion cells from apoptosis, suggesting that upregulation of SOCS3 may be a common physiologic response of neuroretinal cells to cellular stress. CONCLUSIONS-Our data suggest two-sided roles of SOCS proteins in retina. Whereas SOCS proteins may improve glucose metabolism, mitigate deleterious effects of inflammation, and promote neuroprotection, persistent SOCS3 expression caused by chronic inflammation or cellular stress can induce insulin resistance and inhibit neurotrophic factors, such as ciliary neurotrophic factor, leukemia inhibitory factor, and insulin, that are essential for retinal cell survival.

Retinal cells suppress intraocular inflammation (uveitis) through production of interleukin-27 and interleukin-10

“…29,30 Interleukin-10 is a potent inducer of SOCS3 [31][32][33] and SOCS proteins have recently been shown to have neuroprotective functions in the retina. 34,35 Our current data showing induction of SOCS1 expression in retina cells by IL-27, suggest that in addition to inhibiting uveitogenic T-cell expansion, up-regulation of SOCS1 and SOCS3 by IL-27 and IL-10, respectively, may render retina cells unresponsive to cytokine signals, thereby conferring protection from prolonged exposure to pro-inflammatory cytokines produced in chronic intraocular inflammatory diseases.…”

Overexpression of miR-200c Induces Chemoresistance in Esophageal Cancers Mediated Through Activation of the Akt Signaling Pathway

“…To explore the mechanism through which downregulation of miR-200c reduces the expression of Akt, we searched again for potential direct target(s) of miR-200c that is (are) involved in the regulation of Akt signaling by using the Target Scan and miRBase Targets database. Thus, in these experiments, we examined the expression of several potential miR-200c targets, such as PPP2CA, PPP2R1B, SOCS6, and A20, all of which are known to negatively regulate Akt signaling (21)(22)(23). Knockdown of miR-200c expression resulted in increased expression of PPP2R1B, a subunit of protein phosphatase 2A (PP2A), which is known to inhibit the phosphorylation of Akt (21), at 48 hours after treatment (Fig.…”

Neuropeptides, Trophic Factors, and Other Substances Providing Morphofunctional and Metabolic Protection in Experimental Models of Diabetic Retinopathy

“…However, recent observations led to the conclusion that inflammation may precede or at least runs parallel with the vascular and neural events ( Joussen et al, 2004;Liu et al, 2008;Tang and Kern, 2011).…”

“…The interplay between the neuroretina and the vasculature is critical in developing neurological symptoms of disease. In DR, the rate of neuronal loss in the retina is slow, leading to a gradual, cumulative reduction mostly in amacrine and ganglion cells (Liu et al, 2008). Two forms of DR can be clearly distinguished: an early, nonproliferative DR, when neovascularization of the macula is not evident, and proliferative DR where the symptoms include macular neovascularization.…”

“…Patients suffering from DR experience gradual vision loss; after ERG deterioration, the visually evoked potentials (VEPs) also start to decrease (Wolff et al, 2010), which indicates cortical dysfunction. However, recent observations led to the conclusion that inflammation may precede or at least runs parallel with the vascular and neural events ( Joussen et al, 2004;Liu et al, 2008;Tang and Kern, 2011).…”