PPARγ downregulation by TGFß in fibroblast and impaired expression and function in systemic sclerosis: a novel mechanism for progressive fibrogenesis.
The nuclear orphan receptor peroxisome proliferator-activated receptor-gamma (PPAR-γ) is expressed in multiple cell types in addition to adipocytes. Upon its activation by natural ligands such as fatty acids and eicosanoids, or by synthetic agonists such as rosiglitazone, PPAR-γ regulates adipogenesis, glucose uptake and inflammatory responses. Recent studies establish a novel role for PPAR-γ signaling as an endogenous mechanism for regulating transforming growth factor-ß (TGF-ß)-dependent fibrogenesis. Here, we sought to characterize PPAR-γ function in the prototypic fibrosing disorder systemic sclerosis (SSc), and delineate the factors governing PPAR-γ expression. We report that PPAR-γ levels were markedly diminished in skin and lung biopsies from patients with SSc, and in fibroblasts explanted from the lesional skin. In normal fibroblasts, treatment with TGF-ß resulted in a time- and dose-dependent down-regulation of PPAR-γ expression. Inhibition occurred at the transcriptional level and was mediated via canonical Smad signal transduction. Genome-wide expression profiling of SSc skin biopsies revealed a marked attenuation of PPAR-γ levels and transcriptional activity in a subset of patients with diffuse cutaneous SSc, which was correlated with the presence of a "TGF-ß responsive gene signature" in these biopsies. Together, these results demonstrate that the expression and function of PPAR-γ are impaired in SSc, and reveal the existence of a reciprocal inhibitory cross-talk between TGF-ß activation and PPAR-γ signaling in the context of fibrogenesis. In light of the potent anti-fibrotic effects attributed to PPAR-γ, these observations lead us to propose that excessive TGF-ß activity in SSc accounts for impaired PPAR-γ function, which in turn contributes to unchecked fibroblast activation and progressive fibrosis.
Division of Rheumatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.
Jun
J
Wei
Asish K
AK
Ghosh
Jennifer L
JL
Sargent
Kazuhiro
K
Komura
Minghua
M
Wu
Qi-Quan
QQ
Huang
Manu
M
Jain
Michael L
ML
Whitfield
Carol
C
Feghali-Bostwick
John
J
Varga
D050156:Adipogenesis / Q000187:drug effects; D000328:Adult; D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism; D005355:Fibrosis / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012595:Scleroderma, Systemic / Q000235:genetics / Q000378:metabolism*; D012867:Skin / Q000378:metabolism / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D047495:PPAR gamma; D016212:Transforming Growth Factor beta