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M. Mailankot, S. Howell, R. H. Nagaraj; Kynurenine Inhibits Fibroblast Growth Factor-2 Mediated Expression of Crystallins and MIP26 in Lens Epithelial Cells. Invest. Ophthalmol. Vis. Sci. 2010;51(13):4772.
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© ARVO (1962-2015); The Authors (2016-present)
Fibroblast growth factor-2 (FGF2)-mediated signaling plays an important role in fiber cell differentiation in the lens. We had previously shown that high levels of kynurenine (KYN) produced from the overexpression of indoleamine 2,3-dioxygenase (IDO) causes defects in the differentiation of fiber cells, induces fiber cell apoptosis and cataract formation in the mouse lens, and leads to cell cycle arrest in cultured mouse epithelial cells (mLEC). In this study, we have investigated effects of KYN on protein expression in mLEC.
mLEC from wild (WT) and IDO transgenic (IDOTg) were treated with 100 ng/ml FGF2 for 5 days in the presence or absence of an IDO inhibitor. We determined expression of crystallins and MIP26 by ELISA, western blotting and immunofluorescence. Effect of KYN on FGF2 signaling was determined by western blotting for phospho proteins.
Exogenous KYN reduces FGF2-mediated expression of α-, β- and γ-crystallin and MIP26 in WT mLEC. We show that endogenously produced KYN in mLEC of IDOTg causes similar defects in FGF2-induced protein expression and that a competitive inhibitor of IDO prevents such defects. Our data also show that exogenous KYN in WT and endogenous KYN in IDOTg inhibit FGF2-induced Akt and ERK1/2 phosphorylation in mLEC, both of which are necessary for crystallin and MIP26 expression in the lens. KYN does not inhibit FGF2 binding to cells but rather chemically modifies a FGF2 receptor (FGFR1) and inhibits its phosphorylation in mLEC.
Together our data show that KYN inhibits FGF2-mediated signaling by chemically modifying FGFR1 and prevents expression of crystallins and MIP26. Our studies provide a novel mechanism by which KYN can exert deleterious effects in the lens.
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