Published online before print July 25, 2002, doi: 10.1161/01.RES.0000031271.20771.4F
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© 2002 American Heart Association, Inc.
Integrative Physiology |
Vascular Inflammation Is Negatively Autoregulated by Interaction Between CCAAT/Enhancer-Binding Protein-
and Peroxisome Proliferator-Activated Receptor-
From the Second Department of Internal Medicine, Ehime University School of Medicine, Ehime, Japan.
Correspondence to Yutaka Kitami, MD, PhD, The Second Department of Internal Medicine, Ehime University School of Medicine, Ehime 791-0295, Japan. 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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