Published online before print July 25, 2002, doi: 10.1161/01.RES.0000031271.20771.4F
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Submitted on November 6, 2001
Revised on July 3, 2002
Accepted on July 17, 2002
Vascular Inflammation Is Negatively Autoregulated by Interaction Between CCAAT/Enhancer-Binding Protein-
and Peroxisome Proliferator-Activated Receptor-
Yasunori Takata ;
From the Second Department of Internal Medicine, Ehime University School of Medicine, Ehime, Japan.
* To whom correspondence should be addressed. E-mail: kitamiyk{at}m.ehime-u.ac.jp.
CCAAT/enhancer-binding proteins (C/EBPs) upregulate transcription of various inflammatory cytokines and acute phase proteins, such as interleukin (IL)-1ß, IL-6, tumor necrosis factor-
, and cyclooxygenase-2. Recent studies have demonstrated that peroxisome proliferator--activated receptor (PPAR)- is present in atherosclerotic lesions, and negatively regulates expression of these genes. Interestingly, PPAR- gene promoter has tandem repeats of C/EBP-binding motif, and C/EBP- plays a pivotal role in transactivation of PPAR- gene. It has been well known that the interaction between C/EBPs and PPAR- plays a central role in maintaining adipocyte differentiation and glucometabolism; however, the relationship between PPAR- and C/EBPs in the vessel wall remains unclear. In the present study, we showed that a high level of C/EBP- expression induced by inflammation positively regulated transcription and protein expression of PPAR- in vascular smooth muscle cells (VSMCs). On the other hand, PPAR- ligands troglitazone, pioglitazone, and 15-deoxy-
12,14-prostaglandin J2 inhibited IL-1ß-induced IL-6 expression at a transcriptional revel in VSMCs. Functional promoter analysis revealed that PPAR- ligands inhibited IL-1ß--induced transactivation of IL-6 gene via suppression of not only nuclear factor-
B but also C/EBP-DNA binding. Moreover, PPAR- ligands suppressed protein expression and transcription of C/EBP- through dephosphorylation of signal transducer and activator of transcription 3. These findings strongly suggest that C/EBP- is negatively autoregulated via transactivation of PPAR-. This feedback mechanism probably downregulates transcription of inflammatory cytokines and acute phase proteins, and modulates inflammatory responses in the early process of atherosclerosis.
Key words: CCAAT/enhancer-binding proteins • peroxisome proliferator-activated receptor-
•
interleukin-6 •
vascular smooth muscle cells •
signal transducer and activator of transcription 3
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