Vascular inflammation is negatively autoregulated by interaction between CCAAT/enhancer-binding protein-δ and peroxisome proliferator-activated receptor-γ

Y Takata, Y Kitami, ZH Yang, M Nakamura… - Circulation …, 2002 - Am Heart Assoc
Y Takata, Y Kitami, ZH Yang, M Nakamura, T Okura, K Hiwada
Circulation research, 2002Am Heart Assoc
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 …
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-Δ12,14-prostaglandin J2 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.
Am Heart Assoc