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Novel Regulation of Cyclooxygenase-2 Expression and Prostaglandin E₂ Production by IFN- in Human Macrophages¹

Institute of Parasitology, McGill University, Quebec, Canada

Cyclooxygenase-2 (COX-2) is the inducible enzyme in macrophages responsible for high output PG production during inflammation and immune responses. Although several stimuli are known to regulate COX-2, the molecular mechanisms modulating its expression by the cytokine network are poorly understood. As IFN- priming is essential for macrophage accessory and effector cell functions, we investigated the effect of IFN- on COX-2 expression in U937 human macrophages stimulated with IL-1ß. A dose- and time-dependent increase in COX-2 mRNA and protein expression was evoked by IL-1ß, whereas the levels of COX-1, the constitutively expressed isoform, remained unaltered. Interestingly, IFN--primed cells showed 40 to 60% lower levels of COX-2 mRNA, protein expression, and PGE₂ production as compared with nonprimed cells. IFN--priming (50–500 U/ml) down-regulated COX-2 expression in a time- and dose-dependent fashion. Furthermore, IFN- inhibited COX-2 gene transcription in response to IL-1ß but not to LPS. In contrast, the rate of decay of COX-2 transcripts in nonprimed and primed macrophages was similar (t_1/2 = 3.2 h). The down-regulatory effect of IFN- on IL-1ß-induced COX-2 expression was abrogated with cycloheximide. These results highlight a novel mechanism of COX-2 regulation by IFN- at the transcriptional level, which may affect the outcome of inflammatory and immune conditions.

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