JNK inhibitor SP600125 reduces COX-2 expression by attenuating mRNA in activated murine J774 macrophages.
Inducible prostaglandin synthase (cyclooxygenase-2, COX-2) is highly expressed in inflammation. The signaling mechanisms involved in the up-regulation of COX-2 are not known in detail. In the present study we investigated the role of c-Jun NH2-terminal kinase (JNK), a member of the mitogen-activated protein kinase (MAPK) family in COX-2 expression and prostaglandin (PG) E2 production in murine J774 macrophages activated by bacterial lipopolysaccharide (LPS). LPS caused a transient activation of JNK which was followed by increased COX-2 expression. Anthra(1,9-cd)pyrazol-6(2H)-one (SP600125), an inhibitor of JNK, inhibited phosphorylation of c-Jun with an IC50 of 5-10 microM. At the same concentrations SP600125 suppressed also LPS-induced COX-2 protein levels and PGE2 production. SP600125 did not alter LPS-induced COX-2 mRNA levels when measured 3 h after addition of LPS, whereas mRNA levels were significantly reduced in SP600125-treated cells when measured 24 h after addition of LPS. LPS-induced COX-2 mRNA levels reduced faster in cells treated with SP600125 than in control cells. Cycloheximide (that is known to activate JNK) enhanced COX-2 expression and its effect was inhibited by SP600125. The present results suggest that JNK pathway is involved in the up-regulation of COX-2 expression possibly by a mechanism related to the stability of COX-2 mRNA.
Nieminen
Riina
R
The Immunopharmacology Research Group, University of Tampere Medical School, and Tampere University Hospital, Research Unit, FIN-33014, Tampere, Finland.
Lahti
Aleksi
A
Jalonen
Ulla
U
Kankaanranta
Hannu
H
Moilanen
Eeva
E
D000818:Animals; D000873:Anthracenes / Q000494:pharmacology*; D001552:Benzazepines / Q000494:pharmacology; D002460:Cell Line; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors; D003513:Cycloheximide / Q000494:pharmacology; D051546:Cyclooxygenase 2 / Q000235:genetics* / Q000378:metabolism; D003609:Dactinomycin / Q000494:pharmacology; D015232:Dinoprostone / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D007211:Indoles / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D010091:Oximes / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects
D000873:Anthracenes; D001552:Benzazepines; D007211:Indoles; D008070:Lipopolysaccharides; D010091:Oximes; D047428:Protein Kinase Inhibitors; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; C120793:alsterpaullone; C474021:indirubin-3'-monoxime; D003609:Dactinomycin; C432165:pyrazolanthrone; D003513:Cycloheximide; D051546:Cyclooxygenase 2; C495893:Cdk2 protein, mouse; D051357:Cyclin-Dependent Kinase 2; D048031:JNK Mitogen-Activated Protein Kinases; D015232:Dinoprostone