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W. Zhang, C. Patel, M. Rojas, Z. Xu, A. Patel, T. Lemtalsi, R. W. Caldwell, M. Bartoli, R. B. Caldwell; IL-6/STAT3 Pathway is Critically Involved in TNF-Alpha Induced Retinal Vascular Inflammation. Invest. Ophthalmol. Vis. Sci. 2010;51(13):4962.
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© ARVO (1962-2015); The Authors (2016-present)
Vascular inflammation is critically involved in the pathogenesis of a variety of retinal diseases such as diabetic retinopathy and ischemic retinopathy. TNF-α, a potent inflammatory mediator, has been strongly implicated in retinal inflammation. This study was undertaken to define the signaling mechanisms by which TNF-α induces retinal vascular inflammation.
Studies were performed in vitro in TNF-α-treated endothelial cells (ECs) and in vivo in mice treated with TNF-α delivered intravitreally.
TNF-α treatment of ECs induced a robust and sustained increase in STAT3 tyrosine phosphorylation which peaked at 60 min and was accompanied by STAT3 nuclear translocation. In contrast, TNF-α only weakly activated STAT1 and had no effect on STAT5 or STAT6. Stattic or Stat3-VII, structurally different specific inhibitors for STAT3, dose dependently blocked TNF-α-induced STAT3 phosphorylation and also abolished TNF-α-induced expression of ICAM-1 and VCAM-1. TNF-α-induced STAT3 phosphorylation involved JAK2 activation and required de novo protein synthesis. IL-6 is an important activator of STAT3. Analysis of IL-6 expression revealed that TNF-α induced IL-6 mRNA expression which was initiated at 30 min and reached a peak at 60 min. Correlated with the mRNA increase, TNF-α also induced a 2.1 fold increase in IL-6 protein. Blockade of IL-6 by neutralizing antibodies against IL-6 or IL-6 receptor prominently blocked TNF-α-induced STAT3 phosphorylation. Leukocyte adhesion to the vascular endothelium is a common feature of retinal inflammation and is an important step in leukocyte infiltration. Blockade of STAT3 activation in ECs by STAT3 inhibitor or IL-6 blockade resulted in more than 79% inhibition of TNF-α-induced monocyte adhesion. In vivo, TNF-α-induced leukocyte adhesion to the retinal vessels was reduced by 54.7% in IL-6 deficient mice.
This research demonstrates that TNF-α induces STAT3 activation in ECs via induction of IL-6 expression. Moreover, IL-6-mediated activation of STAT3 is involved in TNF-α-induced vascular inflammatory reactions. Modulation of the IL6/STAT3 pathway may provide therapeutic benefit for the treatment of retinal vascular inflammation.
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