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C.N. Nagineni, K.S. Cherukuri, V. Kutty, B. Detrick, J.J. Hooks; Interferon– Differentially Regulates Transforming Growth Factor–ß1 and TGF–ß2 Expression in Human Retinal Pigment Epithelial Cells Through JAK Dependent Pathways . Invest. Ophthalmol. Vis. Sci. 2006;47(13):2863.
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© ARVO (1962-2015); The Authors (2016-present)
To study the role of inflammatory cytokines on the expression of TGF–ß1 and TGF–ß2 by human retinal pigment epithelial cells (HRPE) and to evaluate the role of JAK dependent pathways in the regulation of TGF–ßexpression by IFN–γ
HRPE cultures, derived from human donor eyes, were treated with various cytokines in serum free medium. The levels of total (latent and mature) and mature (active) TGF–ßin the culture medium were determined by ELISA. TGF–ßmRNA levels were analyzed by conventional and Real Time PCR. HRPE cultures were treated with IFN–γ, TNF–αand/or IL–1ßin the presence of signal transduction inhibitors to dissect out the pathways involved in the regulation.
TNF–αand IL–1ßenhanced constitutively expressed mRNA levels of both TGF–ß1 and TGF–ß2. IFN–γenhanced TGF–ß1 mRNA but inhibited TGF–ß2 mRNA. Real Time PCR analyses confirmed these results. Almost all of the TGF–ß1 secreted was in a latent form while 10–40 % of the secreted TGF–ß2 was in a mature form. IFN–γenhanced significantly TGF–ß1 secretion while inhibiting TGF–ß2 secretion. TGF– ß3 secretion and mRNA was not detectable under any of these conditions. JAK inhibitor significantly reversed the inhibitory effects on TGF–ß2 secretion caused by IFN–γ alone or in combination with IL1–ßand TNF–α. Under similar conditions, the enhancing effects of IFN–γon TGF–ß1 secretion were inhibited by of JAK inhibitor. In contrast, stimulatory effects of IL–1ßand TNF–αon TGF–ß1 and TGF–ß2 were not significantly affected by JAK inhibitor.
Our results show that the inflammatory mediators regulate TGF–ß1and TGF–ß2expression by HRPE and that IFN –γ effects are mediated through JAK–STAT pathway. The contrasting effects of IFN –γon TGF–ß1 and TGF–ß2expression in HRPE suggest possible differential roles for TGF–ß1and TGF–ß2 in the inflammatory disorders of the retina and choroid.
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