Peroxisome proliferator-activated receptor-gamma activation inhibits interleukin-1beta -mediated platelet-derived growth factor-alpha receptor gene expression via CCAAT/enhancer-binding protein-delta in vascular smooth muscle cells.
CCAAT/enhancer-binding protein (C/EBP)-binding motifs have been identified in the promoter regions of interleukin (IL)-6, tumor necrosis factor-alpha, and platelet-derived growth factor-alpha receptor (PDGFalphaR). Recently, peroxisome proliferator-activated receptors (PPARs) have been suggested to be important immunomodulatory mediators. Although many studies have demonstrated that the interaction between C/EBPs and PPARs plays a central role in lipid metabolism, expression and function of these factors are unknown in vascular smooth muscle cells (VSMCs). In the present study, we clarified a functional relationship between C/EBPs and PPARgamma in the regulation of IL-1beta-induced PDGFalphaR expression in VSMCs. PPARgamma activators, troglitazone and 15-deoxy-Delta(12,14)-prostaglandin J(2), inhibited IL-1beta-induced PDGFalphaR expression and suppressed PDGF-induced proliferation activity of VSMCs. Electromobility shift and supershift assays for a C/EBP motif in the PDGFalphaR promoter region revealed that PPARgamma activators suppressed IL-1beta-induced DNA binding activity of C/EBPdelta and beta. PPARgamma activators also suppressed IL-1beta-induced C/EBPdelta expression. In contrast, overexpression of C/EBPdelta reversed the suppressive effect of PPARgamma activators on PDGFalphaR expression almost completely. From these results, we conclude that the inhibitory effect of PPARgamma activators on PDGFalphaR expression is mainly mediated by C/EBPdelta suppression. Regulation of C/EBPdelta by PPARgamma activators probably plays critical roles in modulating inflammatory responses in the arterial wall.
Takata
Y
Y
Second Department of Internal Medicine, Ehime University School of Medicine, Ehime 791-0295, Japan.
Kitami
Y
Y
Okura
T
T
Hiwada
K
K
D000818:Animals; D001013:Aorta, Thoracic / Q000166:cytology / Q000502:physiology; D051743:CCAAT-Enhancer-Binding Protein-delta; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D002839:Chromans / Q000494:pharmacology*; D015237:Dinoprost / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics*; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects / Q000502:physiology*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D000077288:Troglitazone
D022762:CCAAT-Enhancer-Binding Proteins; C497252:CEBPD protein, human; C497254:Cebpd protein, rat; D002839:Chromans; D007375:Interleukin-1; D010975:Platelet Aggregation Inhibitors; D018160:Receptors, Cytoplasmic and Nuclear; D011994:Recombinant Proteins; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D051743:CCAAT-Enhancer-Binding Protein-delta; D015237:Dinoprost; D020796:Receptor, Platelet-Derived Growth Factor alpha; D000077288:Troglitazone