Inhibition of Interleukin-1β-Induced Group IIA Secretory Phospholipase A2 Expression by Peroxisome Proliferator-Activated Receptors (PPARs) in Rat Vascular Smooth Muscle Cells: Cooperation between PPARβ and the Proto-Oncogene BCL-6

Abstract

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-1β-induced sPLA2-IIA promoter activity was inhibited by the three PPAR ligands and in a similar way when cells were cotransfected with PPARα, PPARβ, or PPARγ, plus retinoid X receptor α (RXRα). Our study revealed that the regulation of sPLA2-IIA gene transcription by PPARα/RXR and PPARγ/RXR heterodimers requires an interaction with a PPAR response element (PPRE) of the sPLA2-IIA promoter. In contrast, PPARβ operates through a PPRE-independent mechanism. In addition, we demonstrated that VSMCs expressed the transcriptional repressor BCL-6. Overexpression of BCL-6 markedly reduced sPLA2-IIA promoter activity in VSMCs, while a dominant negative form of BCL-6 abrogated sPLA2 repression by PPARβ. The PPARβ 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 PPARβ ligand on sPLA2 activity and prostaglandin E₂ release. Thus, the inhibition of sPLA2-IIA activity by PPARβ agonists may provide a promising approach to impacting the initiation and progression of atherosclerosis.

This work was supported by the Centre National de la Recherche Scientifique and the Université Pierre et Marie Curie. L.R. was supported by doctoral fellowships from the French Ministère de l'Education Nationale, de la Recherche et de la Technologie.

We gratefully thank Ari Melnick (Department of Developmental and Molecular Biology of Albert Einstein College of Medecine) for providing the BCL-6 plasmids. We thank Walter Wahli (Center for Integrative Genomics, University of Lausanne) for providing us the PPRE-TK-Luc construct and PPAR expression vectors. The English text was edited by Paul Lazarow.