Essential role of Smad3 in the inhibition of inflammation-induced PPARbeta/delta expression.
Wound healing proceeds by the concerted action of a variety of signals that have been well identified. However, the mechanisms integrating them and coordinating their effects are poorly known. Herein, we reveal how PPARbeta/delta (PPAR: peroxisome proliferator-activated receptor) follows a balanced pattern of expression controlled by a crosstalk between inflammatory cytokines and TGF-beta1. Whereas conditions that mimic the initial inflammatory events stimulate PPARbeta/delta expression, TGF-beta1/Smad3 suppresses this inflammation-induced PPARbeta/delta transcription, as seen in the late re-epithelialization/remodeling events. This TGF-beta1/Smad3 action involves an inhibitory effect on AP-1 activity and DNA binding that results in an inhibition of the AP-1-driven induction of the PPARbeta/delta promoter. As expected from these observations, wound biopsies from Smad3-null mice showed sustained PPARbeta expression as compared to those of their wild-type littermates. Together, these findings suggest a mechanism for setting the necessary balance between inflammatory signals, which trigger PPARbeta/delta expression, and TGF-beta1/Smad3 that governs the timely decrease of this expression as wound healing proceeds to completion.
Center for Integrative Genomics, NCCR Frontiers in Genetics, University of Lausanne, 1015 Lausanne, Switzerland.
Nguan Soon
NS
Tan
Liliane
L
Michalik
Nicolas
N
Di-Poï
Chuan Young
CY
Ng
Nicolas
N
Mermod
Anita B
AB
Roberts
Béatrice
B
Desvergne
Walter
W
Wahli
D000818:Animals; D002460:Cell Line; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D007249:Inflammation / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000378:metabolism; D047494:PPAR delta / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D048068:PPAR-beta / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D015398:Signal Transduction; D051900:Smad3 Protein; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1; D014945:Wound Healing / Q000502:physiology
D016207:Cytokines; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D047494:PPAR delta; D048068:PPAR-beta; D016755:Proto-Oncogene Proteins c-jun; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; C508961:Tgfb1 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1