Antifibrotic Actions of Peroxisome Proliferator Activated Receptor gamma Ligands in Corneal Fibroblasts Are Mediated by beta-Catenin-Regulated Pathways

作者：Jeon Kye Im; Phipps Richard P; Sime Patricia J; Huxlin Krystel R^*

来源：American Journal Of Pathology, 2017, 187(8): 1660-1669.

DOI：10.1016/j.ajpath.2017.04.002

Wound healing after corneal injury typically involves fibrosis, with transforming growth factor beta 1 (TGF-beta 1) as one of its strongest mediators. A class of small molecules peroxisome proliferator activated receptor gamma (PPAR gamma) Ligands-exert potent antifibrotic effects in the cornea by blocking phosphorylation of p38 mitogen-activated protein kinase (MAPK). However, why this blocks fibrosis remains unknown. Herein, we show that PPAR gamma ligands (rosigLitazone, troglitazone, and 15-deoxy-Delta 12,14-prostaglandin J2) decrease Levels of P-catenin. We also show that beta-catenin siRNA and the Wingless/integrated (Wnt) inhibitor pyrvinium block the ability of corneal fibroblasts to up-regulate synthesis of alpha-smooth muscle actin (alpha-SMA), collagen 1 (COL1), and fibronectin (FN) in response to TGF-beta 1. Activation of TGF-beta receptors and p38 MAPK increased glycogen synthase kinase 3 beta (GSK3 beta) phosphorylation, whereas a chemical inhibitor of p38 MAPK (SB203580) reduced the phosphorylation of GSK3 beta, decreasing active beta-catenin levels in both cytoplasmic and nuclear fractions. Finally, Lithium chloride, a GSK3 inhibitor, also attenuated the TGF-beta 1 induced increase in a-SMA, COL1, and FN expression. All in all, our results suggest that TGF-beta 1 stimulation increases active P-catenin concentration in cultured corneal fibroblasts through p38 MAPK regulation of canonical Wnt/beta-catenin signaling, increasing a-SMA, COL1, and FN synthesis. Thus, PPAR gamma ligands, by blocking TGF-beta 1 induced p38 MAPK phosphorylation, prevent increases in both total and active P-catenin through p38 MAPK-GSK3 beta signaling.