Interleukin 1β Induces Type II-secreted Phospholipase A2 Gene in Vascular Smooth Muscle Cells by a Nuclear Factor κB and Peroxisome Proliferator-activated Receptor-mediated Process

• Published in: The Journal of biological chemistry 1999-08, Vol.274 (33), p.23085-23093
• Main Authors: Couturier, Cyril, Brouillet, Arthur, Couriaud, Cécile, Koumanov, Kamen, Béréziat, Gilbert, Andréani, Marise
• Format: Article
• Language: English
• Subjects: Cellular Biology; Life Sciences
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.274.33.23085

Type II-secreted phospholipase A2 (type II-sPLA2) is expressed in smooth muscle cells during atherosclerosis or in response to interleukin-1β. The present study shows that the induction of type II-sPLA2gene by interleukin-1β requires activation of the NFκB pathway and cytosolic PLA2/PPARγ pathway, which are both necessary to achieve the transcriptional process. Interleukin-1β induced type II-sPLA2 gene dose- and time-dependently and increased the binding of NFκB to a specific site of type II-sPLA2 promoter. This effect was abolished by proteinase inhibitors that block the proteasome machinery and NFκB nuclear translocation. Type II-sPLA2 induction was also obtained by free arachidonic acid and was blocked by either AACOCF3, a specific cytosolic-PLA2 inhibitor, PD98059, a mitogen-activated protein kinase kinase inhibitor which prevents cytosolic PLA2 activation, or nordihydroguaiaretic acid, a lipoxygenase inhibitor, but not by the cyclooxygenase inhibitor indomethacin, suggesting a role for a lipoxygenase product. Type II-sPLA2 induction was obtained after treatment of the cells by 15-deoxy-Δ12,14-dehydroprostaglandin J2, carbaprostacyclin, and 9-hydroxyoctadecadienoic acid, which are ligands of peroxisome proliferator-activated receptor (PPAR) γ, whereas PPARα ligands were ineffective. Interleukin-1β as well as PPARγ-ligands stimulated the activity of a reporter gene containing PPARγ-binding sites in its promoter. Binding of both NFκB and PPARγ to their promoter is required to stimulate the transcriptional process since inhibitors of each class block interleukin-1β-induced type II-sPLA2 gene activation. We therefore suggest that NFκB and PPARγ cooperate at the enhanceosome-coactivator level to turn on transcription of the proinflammatory type II-sPLA2 gene.