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-l imiting enzyme in the conversion of arachidonic acid to prostanoids, h as two isoforms, PGHS-1 is constitutively expressed and involved in ho meostasis, whereas PGHS-2 is inducible in monocytes in response to pro inflammatory agents. Using freshly elutriated human monocytes, we exam ined the effect on PGHS-2 expression of certain cytokine-suppressive a nti-inflammatory drugs such as SK&F 86002. Incubation with serum-treat ed zymosan (STZ) stimulated the expression of PGHS-2 in a time- and do se-dependent manner. SK&F 86002 dose-dependently inhibited this STZ-in duced expression of PGHS-2 protein, which correlated with a decrease i n prostaglandin E-2 and thromboxane A(2) production. However, suppress ion of PGHS-2 expression is not the result of suppressed cytokine prod uction, because SK&F 86002 suppressed PGHS-2 expression initiated by I L-1 beta and TNF-alpha, in addition to other stimuli. Moreover, this e ffect was selective in that the protein expression of two other import ant enzymes involved in the metabolism of arachidonic acid, cytosolic phospholipase A(2) and 5-lipoxygenase, was not affected. Stimulation w ith STZ caused a time-dependent increase in levels of PGHS-2 mRNA; inc ubation with cytokine-suppressive agents caused a decrease of these le vels, suggesting the involvement of transcription and/or mRNA stabilit y events in the inhibition of PGHS-2. These results indicate a new and potentially important anti-inflammatory property of SK&F 86002, namel y the specific suppression of PGHS-2 induction.