Inhibition of prostaglandin endoperoxide synthase-2 expression in stimulated human monocytes by inhibitors of p38 mitogen-activated protein kinase.
Prostaglandin endoperoxide synthase (PGHS; cyclooxygenase), the rate-limiting enzyme in the conversion of arachidonic acid to prostanoids, has two isoforms. PGHS-1 is constitutively expressed and involved in homeostasis, whereas PGHS-2 is inducible in monocytes in response to proinflammatory agents. Using freshly elutriated human monocytes, we examined the effect on PGHS-2 expression of certain cytokine-suppressive anti-inflammatory drugs such as SK&F 86002. Incubation with serum-treated zymosan (STZ) stimulated the expression of PGHS-2 in a time- and dose-dependent manner. SK&F 86002 dose-dependently inhibited this STZ-induced expression of PGHS-2 protein, which correlated with a decrease in prostaglandin E2 and thromboxane A2 production. However, suppression of PGHS-2 expression is not the result of suppressed cytokine production, because SK&F 86002 suppressed PGHS-2 expression initiated by IL-1beta and TNF-alpha, in addition to other stimuli. Moreover, this effect was selective in that the protein expression of two other important enzymes involved in the metabolism of arachidonic acid, cytosolic phospholipase A2 and 5-lipoxygenase, was not affected. Stimulation with STZ caused a time-dependent increase in levels of PGHS-2 mRNA; incubation with cytokine-suppressive agents caused a decrease of these levels, suggesting the involvement of transcription and/or mRNA stability events in the inhibition of PGHS-2. These results indicate a new and potentially important anti-inflammatory property of SK&F 86002, namely the specific suppression of PGHS-2 induction.
Pouliot
M
M
Rheumatology Unit, Royal Adelaide Hospital, South Australia. marc@field.medicine.adelaide.edu.au
Baillargeon
J
J
Lee
J C
JC
Cleland
L G
LG
James
M J
MJ
D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors*; D002478:Cells, Cultured; D016861:Cyclooxygenase Inhibitors / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases; D009000:Monocytes / Q000201:enzymology*; D010741:Phospholipases A / Q000378:metabolism; D054467:Phospholipases A2; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D013844:Thiazoles / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases
D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D007093:Imidazoles; D007375:Interleukin-1; D011725:Pyridines; D012333:RNA, Messenger; D013844:Thiazoles; C052026:6-(4-fluorophenyl)-2,3-dihydro-5-(4-pyridinyl)imidazo(2,1-b)thiazole; D001094:Arachidonate 5-Lipoxygenase; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D010741:Phospholipases A; D054467:Phospholipases A2; C093642:SB 203580