Sodium salicylate enhances the expression of cyclooxygenase-2 in endotoxin-stimulated human mononuclear cells.
The effects of salicylate on the expression of cyclooxygenases, and on prostaglandin E(2) biosynthesis were examined in human peripheral blood mononuclear cells. Peripheral blood mononuclear cells were incubated in the presence of endotoxin, which induced expression of cyclooxygenase-2 protein, and caused a time-dependent increase of immunoreactive prostaglandin E(2) in the supernatant. The cycooxygenase-2 selective inhibitor N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide (NS-398, 1 microM) suppressed the endotoxin-induced increase of prostaglandin E(2), without significantly affecting the expression of cyclooxygenase-1 or cyclooxygenase-2. In peripheral blood mononuclear cells exposed to endotoxin (18 h), 1.0 and 3.0 mM sodium salicylate reduced the prostaglandin E(2) concentration of the supernatant, and, at the same time, stimulated cyclooxygenase-2 expression. After a subsequent 2 h incubation of peripheral blood mononuclear cells in drug-free medium, prostaglandin E(2) concentrations in samples that had been exposed to endotoxin together with 1.0 or 3.0 mM salicylate were significantly higher than in samples exposed to endotoxin alone. These results show that salicylate can enhance the expression of cyclooxygenase-2 in endotoxin-exposed peripheral blood mononuclear cells and at the same time reduce prostaglandin E(2) formation. After washout and removal of salicylate-induced cyclooxygenase inhibition, increased cyclooxygenase-2 expression resulted in enhanced prostaglandin E(2) formation. It seems possible that under certain conditions salicylate-induced stimulation of cyclooxygenase-2 expression may contribute to its clinical pharmacological profile.
Amann
R
R
Institute for Experimental and Clinical Pharmacology, University of Graz, University Platz 4, A-8010 Graz, Austria.
Egger
T
T
Schuligoi
R
R
Heinemann
A
A
Peskar
B A
BA
D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000096:biosynthesis; D004731:Endotoxins / Q000494:pharmacology*; D006801:Humans; D007527:Isoenzymes / Q000096:biosynthesis*; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000201:enzymology; D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis*; D012980:Sodium Salicylate / Q000494:pharmacology*
D004731:Endotoxins; D007527:Isoenzymes; D008565:Membrane Proteins; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone; D012980:Sodium Salicylate