期刊
CIRCULATION RESEARCH
卷 91, 期 5, 页码 427-433出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/01.RES.0000031271.20771.4F
关键词
CCAAT/enhancer-binding proteins; peroxisome proliferator-activated receptor-gamma; interleukin-6; vascular smooth muscle cells; signal transducer and activator of transcription 3
CCAAT/enhancer-binding proteins (C/EBPs) upregulate transcription of various inflammatory cytokines and acute phase proteins, such as interleukin (IL)-1beta, IL-6, tumor necrosis factor-alpha, and cyclooxygenase-2. Recent studies have demonstrated that peroxisome proliferator-activated receptor (PPAR)-gamma is present in atherosclerotic lesions, and negatively regulates expression of these genes. Interestingly, PPAR-gamma gene promoter has tandem repeats of C/EBP-binding motif, and C/EBP-8 plays a pivotal role in transactivation of PPAR-,y gene. It has been well known that the interaction between C/EBPs and PPAR-gamma plays a central role in maintaining adipocyte differentiation and glucometabolism; however, the relationship between PPAR-gamma and C/EBPs in the vessel wall remains unclear. In the present study, we showed that a high level of C/EBP-5 expression induced by inflammation positively regulated transcription and protein expression of PPAR-gamma in vascular smooth muscle cells (VSMCs). On the other hand, PPAR-gamma ligands troglitazone, pioglitazone, and 15-deoxy-Delta(12,14)-prostaglandin J(2) inhibited IL-1beta-induced IL-6 expression at a transcriptional revel in VSMCs. Functional promoter analysis revealed that PPAR-gamma ligands inhibited IL-1beta-induced transactivation of IL-6 gene via suppression of not only nuclear factor-kappaB but also C/EBP-DNA binding. Moreover, PPAR-gamma ligands suppressed protein expression and transcription of C/EBP-5 through dephosphorylation of signal transducer and activator of transcription 3. These findings strongly suggest that C/EBP-5 is negatively autoregulated via transactivation of PPAR-gamma. This feedback mechanism probably downregulates transcription of inflammatory cytokines and acute phase proteins, and modulates inflammatory responses in the early process of atherosclerosis.
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