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C. Bloquel, R.A. Bejjani, B. Thillaye–Goldenberg, M. Doat, D. BenEzra, D. Scherman, F. Behar–Cohen; Mechanistic Study of TNF–Alpha Role in Endotoxin–Induced Uveitis by Neutralization of TNF–Alpha Thanks to TNF–Alpha Soluble Receptor Plasmid Electrotransfer . Invest. Ophthalmol. Vis. Sci. 2006;47(13):2606.
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© ARVO (1962-2015); The Authors (2016-present)
TNF–alpha is one of the major cytokines involved in uveitis. During endotoxin–induced uveitis (EIU), increased levels of TNF–alpha are found in aqueous humor. Treatment of EIU by ciliary muscle electrotransfer with a TNFR–Is/IgG1 encoding plasmid was proven efficient. The current study was designed to investigate the effect of TNF–alpha on cytokines and chemokines profile expression, and on apoptotic cell death in EIU in rats.
EIU was induced in Lewis rats by a single footpad injection of 150 µg Salmonella Typhimurium lipopolysaccharide (LPS). Rats were treated by electrotransfer in the ciliary muscle of a plasmid encoding a chimeric TNF soluble receptor linked to the Fc fragment of IgG1 (TNFR–Is/IgG1). A single treatment was administred 6 days before the induction of the disease. This treatment has already proven its efficiency in the EIU model by electrotransfer of 3 µg of plasmid. Two and twenty–for hours after induction of the disease, cytokines and chemokines expression in iris and ciliary muscle were evaluated by semi–quantitative RT–PCR. Cell death was evaluated by TUNEL and FasL immunostaining. Activation of macrophages was evaluated by immunostaining.
Two and twenty–for hours after induction of EIU, pro–inflammatory cytokines (IL–6, TNF–alpha, IL–1), chemokines (RANTES, MIP–1, TGF–beta) and iNOS were increased in iris/ciliary muscle of LPS control animals as compared to naïve rats. Treatment with the TNFR–Is/IgG1 encoding plasmid led to significant decrease of IL–6 and iNOs, and to an increase of IL–10, both at two and twenty–for hours after disease induction. Local secretion of TNFR–Is/IgG1 also led to a decrease in cell death.
Our results help at explaining the mechanism of TNF–alpha in EIU. Our data are in agreement with an immunomodulatory role of TNF–alpha, and a switch from a Th1 to a Th2 answer by anti–TNF treatment. TNF–alpha also lead to cell apoptosis, which can be inhibited by TNFR–Is/IgG1 treatment. These results confirm the potential use of anti–TNF as a therapeutic agent for the inhibition of ocular inflammatory processes.
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