Inhibition of TNF? protects the retina against diabetic-like changes in rodent models. The mechanism by which TNF? induces deleterious retinal changes is not known.
Previously, we have shown that TNF? can inhibit normal insulin signal transduction, leading to increased apoptosis in both retinal endothelial cells (REC) and M?ller cells. Additionally, ?2-adrenergic receptor knockout mice (?2KO) have increased TNF? levels and decreased insulin receptor activity.
In this study, we hypothesized that inhibition of TNF? in ?2KO mice would increase normal insulin signaling, leading to improved retinal function.
Methods:
C57BL6 or ?2KO mice were left untreated or treated with etanercept (0.3?mg/kg subcutaneously, 3? a week) for 2?months. Electroretinogram analyses were done before treatment was initiated and after two months of treatment with etanercept on all mice.
Western blot or ELISA analyses were done on whole retinal lysates from all four groups of mice for TNF?, suppressor of cytokine signaling 3 (SOCS3), insulin receptor, and apoptotic proteins.
Results:
Etanercept significantly reduced TNF? levels in ?2KO mice, leading to increased insulin receptor phosphorylation on tyrosine 1150/1151. SOCS3 levels were increased in ?2KO mice, which were reduced after etanercept treatment.
Pro-apoptotic proteins were reduced in etanercept-treated ?2KO mice. Etanercept improved ERG amplitudes in ?2KO mice.
Conclusions:
Inhibition of TNF? by etanercept protects the retina likely through reduced TNF?-mediated insulin resistance, leading to reduced apoptosis.
Author: Youde JiangQiuhua ZhangEun-Ah YeJena J Steinle
Credits/Source: Journal of Neuroinflammation 2014, 11:137
Published on: 2014-08-20
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