Proinflammatory Cytokines Regulate Cyclooxygenase-2 mRNA Expression in Human Macrophages

Abstract

Prostaglandins play a major role in the inflammatory and immune response. Macrophages constitutively produce prostaglandins by the enzyme cyclooxygenase-l (cox) whereas inflammatory mediators and cytokines stimulate the inducible enzyme cox-2 for high output prostaglandin production. In this study, we investigated the effect of LPS, IFN-γ and TNF-α in the regulation of cox-1 and cox-2 mRNA expression in PMA-differentiated U937 human macrophages. LPS, but not IFN-γ or TNF-α, caused the induction of cox-2 mRNA in a dose- and time-dependent fashion. In IFN-γ-primed macrophages, LPS stimulated a marked increase in the accumulation of cox-2 mRNA, whereas TNF-α and IFN-γ induced a moderate level. However, IFN-γ in combination with either LPS or TNF-α induced a synergistic increase in the accumulation of cox-2 mRNA after 24 hours. Regardless of the conditions, cox-1 mRNA remained unchanged. These results indicate that IFN-γ priming is required for full expression of cox-2 mRNA in response to LPS or TNF-α stimulation and suggest that cox-2 mRNA is highly regulated by cytokines during macrophage activation.