Interleukin 1 beta induces type II-secreted phospholipase A(2) gene in vascular smooth muscle cells by a nuclear factor kappa B and peroxisome proliferator-activated receptor-mediated process

Type II-secreted phospholipase A(2) (type II-sPLA(2)) is expressed in smoot h 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 inte rleukin-1 beta requires activation of the NF kappa B pathway and cytosolic PLA(2)/PPAR gamma pathway, which are both necessary to achieve the transcri ptional 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 inhib itors that block the proteasome machinery and NF kappa B nuclear translocat ion. Type II-sPLA(2) induction was also obtained by free arachidonic acid a nd 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 liga nds of peroxisome proliferator-activated receptor (PPAR) gamma, whereas PPA R alpha ligands were ineffective, Interleukin-1 beta as well as PPAR gamma- ligands stimulated the activity of a reporter gene containing PPAR gamma-bi nding sites in its promoter. Binding of both NF kappa B and PPAR gamma to t heir promoter is required to stimulate the transcriptional process since in hibitors of each class block interleukin-1 beta-induced type II-sPLA(2) gen e activation, We therefore suggest that NF kappa B and PPAR gamma cooperate at the enhanceosome-coactivator level to turn on transcription of the proi nflammatory type II-sPLA(2) gene.