Interleukin 1beta induces type II-secreted phospholipase A(2) gene in vascular smooth muscle cells by a nuclear factor kappaB 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-1beta. The present study shows that the induction of type II-sPLA(2) gene by interleukin-1beta requires activation of the NFkappaB pathway and cytosolic PLA(2)/PPARgamma pathway, which are both necessary to achieve the transcriptional process. Interleukin-1beta induced type II-sPLA(2) gene dose- and time-dependently and increased the binding of NFkappaB to a specific site of type II-sPLA(2) promoter. This effect was abolished by proteinase inhibitors that block the proteasome machinery and NFkappaB 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)-dehydroprostaglandin J(2), carbaprostacyclin, and 9-hydroxyoctadecadienoic acid, which are ligands of peroxisome proliferator-activated receptor (PPAR) gamma, whereas PPARalpha ligands were ineffective. Interleukin-1beta as well as PPARgamma-ligands stimulated the activity of a reporter gene containing PPARgamma-binding sites in its promoter. Binding of both NFkappaB and PPARgamma to their promoter is required to stimulate the transcriptional process since inhibitors of each class block interleukin-1beta-induced type II-sPLA(2) gene activation. We therefore suggest that NFkappaB and PPARgamma cooperate at the enhanceosome-coactivator level to turn on transcription of the proinflammatory type II-sPLA(2) gene.
Couturier
C
C
Unité Propre de Recherche de l'Université Pierre et Marie Curie, Associée au CNRS, ESA7079, 7 quai St. Bernard, 75252 Paris, Cedex 5, France.
Brouillet
A
A
Couriaud
C
C
Koumanov
K
K
Béréziat
G
G
Andréani
M
M
D000818:Animals; D001483:Base Sequence; D001692:Biological Transport; D002478:Cells, Cultured; D002518:Ceramides / Q000378:metabolism; D003513:Cycloheximide / Q000494:pharmacology; D017931:DNA Primers; D003609:Dactinomycin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D007375:Interleukin-1 / Q000494:pharmacology*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D016328:NF-kappa B / Q000378:metabolism*; D010741:Phospholipases A / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation
D002518:Ceramides; D017931:DNA Primers; D007375:Interleukin-1; D016328:NF-kappa B; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D003609:Dactinomycin; D003513:Cycloheximide; D010741:Phospholipases A; D013108:Sphingomyelin Phosphodiesterase