PROINFLAMMATORY CYTOKINES REGULATE CYCLOOXYGENASE-2, MESSENGER-RNA EXPRESSION IN HUMAN MACROPHAGES

Prostaglandins play a major role in the inflammatory and immune respon se. Macrophages constitutively produce prostaglandins by the enzyme cy clooxygenase-l (cox) whereas inflammatory mediators and cytokines stim ulate the inducible enzyme cox-2 for high output prostaglandin product ion. In this study, we investigated the effect of LPS, IFN-gamma and T NF-alpha in the regulation of cox-1 and cox-2 mRNA expression in PMA-d ifferentiated U937 human macrophages. LPS, but not IFN-gamma or TNF-al pha, caused the induction of cox-2 mRNA in a dose- and time-dependent fashion. In IFN-gamma-primed macrophages, LPS stimulated a marked incr ease in the accumulation of cox-2 mRNA, whereas TNF-alpha and IFN-gamm a induced a moderate level. However, IFN-gamma in combination with eit her LPS or TNF-alpha induced a synergistic increase in the accumulatio n of cox-2 mRNA after 24 hours. Regardless of the conditions, cox-1 mR NA remained unchanged. These results indicate that IFN-gamma priming i s required for full expression of cox-2 mRNA in response to LPS or TNF -alpha stimulation and suggest that cox-2 mRNA is highly regulated by cytokines during macrophage activation. (C) 1995 Academic Press, Inc.