Complement C5b-9 induces cyclooxygenase-2 gene transcription in glomerular epithelial cells.
In rat membranous nephropathy, complement C5b-9 induces glomerular epithelial cell (GEC) injury and proteinuria, which is partially mediated by eicosanoids. Rat GEC in culture express cyclooxygenase (COX)-1 constitutively, whereas COX-2 expression is induced by C5b-9. Both isoforms contribute to complement-induced prostaglandin generation. The present study addresses mechanisms of complement-induced COX-2 expression in GEC. Downregulation of protein kinase C (PKC) blunted complement-induced upregulation of COX-2 mRNA. Complement and phorbol 12-myristate 13-acetate (PMA) both stimulated COX-2 promoter activity. C5b-9 activated c-Jun NH(2)-terminal kinase (JNK), and inhibition of JNK activity by transfection of a kinase-inactive JNK1 partially inhibited complement-induced (but not PMA-induced) COX-2 promoter activation. Conversely, a constitutively active mitogen-activated protein or extracellular signal-regulated kinase kinase kinase (MEKK)-1, a kinase upstream of JNK, increased COX-2 promoter activity. MEKK-induced COX-2 promoter activation was not affected by downregulation of PKC and was augmented by PMA. Thus, in GEC, PKC and JNK pathways contribute independently to complement-induced COX-2 expression. Nuclear factor-kappaB was also activated by complement in GEC but did not contribute to complement-induced COX-2 upregulation.
Takano
T
T
Department of Medicine, McGill University Health Centre, Montreal, Quebec, Canada H3A 2B4. ttomok@po-box.mcgill.ca
Cybulsky
A V
AV
Yang
X
X
Aoudjit
L
L
D000818:Animals; D015938:Complement Membrane Attack Complex / Q000494:pharmacology*; D051546:Cyclooxygenase 2; D004789:Enzyme Activation / Q000187:drug effects; D004847:Epithelial Cells / Q000201:enzymology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D007527:Isoenzymes / Q000235:genetics*; D048031:JNK Mitogen-Activated Protein Kinases; D007678:Kidney Glomerulus / Q000201:enzymology*; D048670:MAP Kinase Kinase 4; D048728:MAP Kinase Kinase Kinase 1; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000502:physiology; D011401:Promoter Regions, Genetic; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics*; D011493:Protein Kinase C / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects*; D014162:Transfection
D015938:Complement Membrane Attack Complex; D007527:Isoenzymes; D016328:NF-kappa B; D012333:RNA, Messenger; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D017346:Protein Serine-Threonine Kinases; D011493:Protein Kinase C; D048031:JNK Mitogen-Activated Protein Kinases; D048728:MAP Kinase Kinase Kinase 1; C482578:Map3k1 protein, mouse; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; D013755:Tetradecanoylphorbol Acetate