%0 Journal Article
%T TGF 1 Controls PPAR Expression, Transcriptional Potential, and Activity, in Part, through Smad3 Signaling in Murine Lung Fibroblasts
%A Allan Ramirez
%A Erin N. Ballard
%A Jesse Roman
%J PPAR Research
%D 2012
%I Hindawi Publishing Corporation
%R 10.1155/2012/375876
%X Transforming growth factor ¦Â1 (TGF¦Â1) promotes fibrosis by, among other mechanisms, activating quiescent fibroblasts into myofibroblasts and increasing the expression of extracellular matrices. Recent work suggests that peroxisome proliferator-activated receptor ¦Ã (PPAR¦Ã) is a negative regulator of TGF¦Â1-induced fibrotic events. We, however, hypothesized that antifibrotic pathways mediated by PPAR¦Ã are influenced by TGF¦Â1, causing an imbalance towards fibrogenesis. Consistent with this, primary murine primary lung fibroblasts responded to TGF¦Â1 with a sustained downregulation of PPAR¦Ã transcripts. This effect was dampened in lung fibroblasts deficient in Smad3, a transcription factor that mediates many of the effects of TGF¦Â1. Paradoxically, TGF¦Â1 stimulated the activation of the PPAR¦Ã gene promoter and induced the phosphorylation of PPAR¦Ã in primary lung fibroblasts. The ability of TGF¦Â1 to modulate the transcriptional activity of PPAR¦Ã was then tested in NIH/3T3 fibroblasts containing a PPAR¦Ã-responsive luciferase reporter. In these cells, stimulation of TGF¦Â1 signals with a constitutively active TGF¦Â1 receptor transgene blunted PPAR¦Ã-dependent reporter expression induced by troglitazone, a PPAR¦Ã activator. Overexpression of PPAR¦Ã prevented TGF¦Â1 repression of troglitazone-induced PPAR¦Ã-dependent gene transcription, whereas coexpression of PPAR¦Ã and Smad3 transgenes recapitulated the TGF¦Â1 effects. We conclude that modulation of PPAR¦Ã is controlled by TGF¦Â1, in part through Smad3 signals, involving regulation of PPAR¦Ã expression and transcriptional potential. 1. Introduction Transforming growth factor ¦Â1 (TGF¦Â1) is a pleomorphic growth factor with anti-inflammatory and profibrotic properties that has been implicated in many forms of natural and experimental tissue fibrosis [1]. In lung, TGF¦Â1 is produced by epithelial cells, alveolar and tissue macrophages, and fibroblasts after exposure to injurious agents such as silica, bleomycin, hyperoxia, and paraquat among others [2]. A key role for TGF¦Â1 in lung fibrosis has been confirmed in studies showing the development of lung fibrosis in animals transfected with TGF¦Â1-producing adenovirus, and by work demonstrating inhibition of experimental lung fibrosis by interventions targeting TGF¦Â1 or its downstream signals [3, 4]. The profibrotic effects of TGF¦Â1 are mostly, but not entirely, mediated by intracellular signals triggered by the transcription factor Smad3 [5]. TGF¦Â1/Smad3 signaling stimulates connective tissue expression and epithelial-mesenchymal transition, events considered key to the development
%U http://www.hindawi.com/journals/ppar/2012/375876/