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

Type II-secreted phospholipase A(2) (type II-sPLA(2)) is expressed in smooth muscle cells during atherosclerosis or in response to interleukin-1 beta. The present study shows that the induction of type II-sPLA(2) gene by interleukin-1 beta requires activation of the NF kappa B pathway and cytosolic PLA(2)/PPAR gamma pathway, which are both necessary to achieve the transcriptional process. Interleukin-1 beta-induced type II-sPLA(2) gene dose- and time-dependently and increased the binding of NF kappa B to a specific site of type II-sPLA(2) promoter. This effect was abolished by proteinase inhibitors that block the proteasome machinery and NF kappa B nuclear translocation. Type II-sPLA(2) induction was also obtained by free arachidonic acid and was blocked by either AACOCF(3), a specific cytosolic-PLA(2) inhibitor, PD98059, a mitogen-activated protein kinase kinase inhibitor which prevents cytosolic PLA(2) activation, or nordihydroguaiaretic acid, a lipoxygenase inhibitor, but not by the cyclooxygenase inhibitor indomethacin, suggesting a role for a lipoxygenase product. Type II-sPLA(2) induction was obtained after treatment of the cells by 15-deoxy-Delta(12,14)-dehydro prostaglandin J(2), carbaprostacyclin, and 9-hydroxyoctadecadienoic acid, which are ligands of peroxisome proliferator-activated receptor (PPAR) gamma, whereas PPAR alpha ligands were ineffective, Interleukin-1 beta as well as PPAR gamma-ligands stimulated the activity of a reporter gene containing PPAR gamma-binding sites in its promoter. Binding of both NF kappa B and PPAR gamma to their promoter is required to stimulate the transcriptional process since inhibitors of each class block interleukin-1 beta-induced type II-sPLA(2) gene activation, We therefore suggest that NF kappa B and PPAR gamma cooperate at the enhanceosome-coactivator level to turn on transcription of the proinflammatory type II-sPLA(2) gene.