Abstract

8 Objectives: A proinflammatory nuclear factor, CCAAT/enhancer-binding protein (C/EBP), regulates transcription of the genes including IL-6, platelet-derived growth factor α-receptor (PDGFαR), leptin, COX-2 and IGF-1 which are closely associated with hypertension, atherosclerosis and insulin resistance. The aim of this study is to investigate the effect of peroxisome proliferator-activated receptor (PPAR)γ activation on cytokine-induced IL-6 and PDGFαR expression, and to clarify underlying mechanisms of the action in vascular smooth muscle cells (VSMCs). Methods and Results: Rat cultured VSMCs were pretreated with troglitazone (TRO) (0-10 μM) or 15-deoxy- 12,14 Δ-prostaglandin J 2 (PGJ 2 ) (0-5 μM) for 24 h, and then stimulated by IL-1β(10 ng/mL) for 6 h. While IL-1β alone markedly induced both protein and mRNA levels of IL-6 and PDGFαR, TRO or PGJ 2 significantly inhibited this induction in a dose-dependent manner. Cell proliferation activity was assessed by measurement of BrdU incorporation after treatment with PDGF. PDGF (20 ng/mL) significantly enhanced cell proliferation activity in IL-1β-stimulated cells whereas this enhanced effect was lost by pretreatment with TRO or PGJ 2 almost completely. Further, electromobility shift assay (EMSA) and supershift assay were performed for a C/EBP binding site that mainly regulates IL-6 and PDGFαR genes transcription. EMSA revealed that IL-1β markedly increased DNA-protein complex formation, and pretreatment with TRO or PGJ 2 reduced it almost completely. Supershift assay demonstrated that the retarded band seen in EMSA was supershifted by antibodies against C/EBPδ. On the other hand, TRO or PGJ 2 significantly suppressed IL-1β-induced C/EBPδ expression, and prostaglandin F 2 α, that acts as an inhibitor of PPARγ, diminished the suppressive effect of PPARγ activators on C/EBPδ expression. Conclusions: The effect of PPARγ activation on IL-6 and PDGFαR expression is mediated by suppression of C/EBPδ expression. These results suggest that cross-regulation of PPARγ and C/EBPδ is beneficial to events of vascular inflammation and resultant vascular remodeling.

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