Abstract—CCAAT/enhancer-binding proteins (C/EBPs) upregulate transcription of various inflammatory cytokines and acute phase proteins, such as interleukin (IL)-1&bgr;, IL-6, tumor necrosis factor-&agr;, and cyclooxygenase-2. Recent studies have demonstrated that peroxisome proliferator-activated receptor (PPAR)-&ggr; is present in atherosclerotic lesions, and negatively regulates expression of these genes. Interestingly, PPAR-&ggr; gene promoter has tandem repeats of C/EBP-binding motif, and C/EBP-&dgr; plays a pivotal role in transactivation of PPAR-&ggr; gene. It has been well known that the interaction between C/EBPs and PPAR-&ggr; plays a central role in maintaining adipocyte differentiation and glucometabolism; however, the relationship between PPAR-&ggr; and C/EBPs in the vessel wall remains unclear. In the present study, we showed that a high level of C/EBP-&dgr; expression induced by inflammation positively regulated transcription and protein expression of PPAR-&ggr; in vascular smooth muscle cells (VSMCs). On the other hand, PPAR-&ggr; ligands troglitazone, pioglitazone, and 15-deoxy-&Dgr;12,14-prostaglandin J2inhibited IL-1&bgr;-induced IL-6 expression at a transcriptional revel in VSMCs. Functional promoter analysis revealed that PPAR-&ggr; ligands inhibited IL-1&bgr;-induced transactivation of IL-6 gene via suppression of not only nuclear factor-&kgr;B but also C/EBP-DNA binding. Moreover, PPAR-&ggr; ligands suppressed protein expression and transcription of C/EBP-&dgr; through dephosphorylation of signal transducer and activator of transcription 3. These findings strongly suggest that C/EBP-&dgr; is negatively autoregulated via transactivation of PPAR-&ggr;. This feedback mechanism probably downregulates transcription of inflammatory cytokines and acute phase proteins, and modulates inflammatory responses in the early process of atherosclerosis.