1. Vascular Inflammation Is Negatively Autoregulated by Interaction Between CCAAT/Enhancer-Binding Protein-δ and Peroxisome Proliferator-Activated Receptor-γ
- Author
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Takafumi Okura, Yasunori Takata, Zhao-Hui Yang, Kunio Hiwada, Michitsugu Nakamura, and Yutaka Kitami
- Subjects
CCAAT-Enhancer-Binding Protein-delta ,Male ,STAT3 Transcription Factor ,medicine.medical_specialty ,Transcription, Genetic ,Physiology ,Recombinant Fusion Proteins ,Receptors, Cytoplasmic and Nuclear ,Peroxisome proliferator-activated receptor ,Biology ,Muscle, Smooth, Vascular ,Rats, Sprague-Dawley ,Troglitazone ,Transactivation ,Internal medicine ,medicine ,Animals ,Chromans ,Phosphorylation ,Luciferases ,Transcription factor ,Cells, Cultured ,Inflammation ,chemistry.chemical_classification ,Ccaat-enhancer-binding proteins ,Interleukin-6 ,Prostaglandin D2 ,NF-kappa B ,Promoter ,Rats ,Cell biology ,DNA-Binding Proteins ,Thiazoles ,Carotid Arteries ,Endocrinology ,Gene Expression Regulation ,chemistry ,CCAAT-Enhancer-Binding Proteins ,Trans-Activators ,STAT protein ,Thiazolidinediones ,Cardiology and Cardiovascular Medicine ,Protein Binding ,Transcription Factors - Abstract
CCAAT/enhancer-binding proteins (C/EBPs) upregulate transcription of various inflammatory cytokines and acute phase proteins, such as interleukin (IL)-1β, IL-6, tumor necrosis factor-α, and cyclooxygenase-2. Recent studies have demonstrated that peroxisome proliferator-activated receptor (PPAR)-γ is present in atherosclerotic lesions, and negatively regulates expression of these genes. Interestingly, PPAR-γ gene promoter has tandem repeats of C/EBP-binding motif, and C/EBP-δ plays a pivotal role in transactivation of PPAR-γ gene. It has been well known that the interaction between C/EBPs and PPAR-γ plays a central role in maintaining adipocyte differentiation and glucometabolism; however, the relationship between PPAR-γ and C/EBPs in the vessel wall remains unclear. In the present study, we showed that a high level of C/EBP-δ expression induced by inflammation positively regulated transcription and protein expression of PPAR-γ in vascular smooth muscle cells (VSMCs). On the other hand, PPAR-γ ligands troglitazone, pioglitazone, and 15-deoxy-Δ 12,14 -prostaglandin J 2 inhibited IL-1β-induced IL-6 expression at a transcriptional revel in VSMCs. Functional promoter analysis revealed that PPAR-γ ligands inhibited IL-1β-induced transactivation of IL-6 gene via suppression of not only nuclear factor-κB but also C/EBP-DNA binding. Moreover, PPAR-γ ligands suppressed protein expression and transcription of C/EBP-δ through dephosphorylation of signal transducer and activator of transcription 3. These findings strongly suggest that C/EBP-δ is negatively autoregulated via transactivation of PPAR-γ. This feedback mechanism probably downregulates transcription of inflammatory cytokines and acute phase proteins, and modulates inflammatory responses in the early process of atherosclerosis.
- Published
- 2002