Vascular inflammation is negatively autoregulated by interaction between CCAAT/enhancer-binding protein-delta and peroxisome proliferator-activated receptor-gamma.
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-delta plays a pivotal role in transactivation of PPAR-gamma 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-delta 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-delta through dephosphorylation of signal transducer and activator of transcription 3. These findings strongly suggest that C/EBP-delta 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.
Takata
Yasunori
Y
Second Department of Internal Medicine, Ehime University School of Medicine, Ehime, Japan.
Kitami
Yutaka
Y
Yang
Zhao-Hui
ZH
Nakamura
Michitsugu
M
Okura
Takafumi
T
Hiwada
Kunio
K
D000818:Animals; D051743:CCAAT-Enhancer-Binding Protein-delta; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D002339:Carotid Arteries / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D002839:Chromans / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D000077288:Troglitazone
D022762:CCAAT-Enhancer-Binding Proteins; C497254:Cebpd protein, rat; D002839:Chromans; D004268:DNA-Binding Proteins; D015850:Interleukin-6; D016328:NF-kappa B; D018160:Receptors, Cytoplasmic and Nuclear; D011993:Recombinant Fusion Proteins; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D013844:Thiazoles; D045162:Thiazolidinediones; D015534:Trans-Activators; D014157:Transcription Factors; D051743:CCAAT-Enhancer-Binding Protein-delta; C037112:9-deoxy-delta-9-prostaglandin D2; D008156:Luciferases; D000077288:Troglitazone; D015230:Prostaglandin D2