Kynurenine inhibits fibroblast growth factor 2-mediated expression of crystallins and MIP26 in lens epithelial cells.
Fibroblast growth factor-2 (FGF2)-mediated signaling plays an important role in fiber cell differentiation in eye lens. We had previously shown that 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 lens epithelial cells (mLEC). In this study, we demonstrate that exogenous KYN reduces FGF2-mediated expression of alpha-, beta-, and gamma-crystallin and MIP26 in mLEC. We show that endogenously produced KYN in mLEC of IDO transgenic animals causes similar defects in FGF2-induced protein expression and that a competitive inhibitor of IDO prevents such defects. Our data also show that KYN inhibits FGF2-induced Akt and ERK1/2 phosphorylation in mLEC, which are required for crystallin and MIP26 expression in the lens. KYN does not inhibit FGF2 binding to cells but inhibit phosphorylation of FGFR1in mLEC. Together our data suggest that KYN might inhibit FGF2-mediated fiber cell differentiation by preventing expression of crystallins and MIP26. Our studies provide a novel mechanism by which KYN can exert deleterious effects in cells.
Mailankot
Maneesh
M
Department of Ophthalmology & Visual Sciences, Case Western Reserve University, Cleveland, OH 44106, USA.
Howell
Scott
S
Nagaraj
Ram H
RH
D000818:Animals; D020346:Aquaporins / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D003459:Crystallins / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects; D004336:Drug Antagonism; D004789:Enzyme Activation / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D005136:Eye Proteins / Q000378:metabolism*; D016222:Fibroblast Growth Factor 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics; D007737:Kynurenine / Q000494:pharmacology*; D007908:Lens, Crystalline / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D051058:Oncogene Protein v-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects
D020346:Aquaporins; D003459:Crystallins; D005136:Eye Proteins; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; C030328:aquaporin 0; D016222:Fibroblast Growth Factor 2; D007737:Kynurenine; D051058:Oncogene Protein v-akt