Inhibition of interleukin-1beta-induced group IIA secretory phospholipase A2 expression by peroxisome proliferator-activated receptors (PPARs) in rat vascular smooth muscle cells: cooperation between PPARbeta and the proto-oncogene BCL-6.

The inflammation that occurs during atherosclerosis is characterized by the release of large amounts of group IIA secretory phospholipase A2 (sPLA2-IIA). This study was designed to define the function of the three peroxisome proliferator-activated receptors (PPARs) on sPLA2 expression in vascular smooth muscle cells (VSMCs). We found that PPAR ligands decreased sPLA2-IIA activity and inhibited mRNA accumulation under inflammatory conditions. Furthermore, interleukin-1 beta-induced sPLA2-IIA promoter activity was inhibited by the three PPAR ligands and in a similar way when cells were cotransfected with PPAR alpha, PPAR beta, or PPAR gamma, plus retinoid X receptor a (RXR alpha). Our study revealed that the regulation of sPLA2-IIA gene transcription by PPAR alpha/RXR and PPAR-gamma/RXR heterodimers requires an interaction with a PPAR response element (PPRE) of the sPLA2-IIA promoter. In contrast, PPAR beta operates through a PPRE-independent mechanism. In addition, we demonstrated that VSMCs expressed the transcriptional repressor BCL-6. Overexpression of BCL-6 markedly reduced sPLA241A promoter activity in VSMCs, while a dominant negative form of BCL-6 abrogated sPLA2 repression by PPAR beta. The PPARP agonist induced a BCL-6 binding to the sPLA2 promoter in VSMCs under inflammatory conditions. The knockdown of BCL-6 by short interfering RNA abolished the inhibitory effect of the PPAR beta ligand on sPLA2 activity and prostaglandin E2 release. Thus, the inhibition of sPLA.2-11A activity by PPAR beta agonists may provide a promising approach to impacting the initiation and progression of atherosclerosis.