NOVEL REGULATION OF CYCLOOXYGENASE-2 EXPRESSION AND PROSTAGLANDIN E-2PRODUCTION BY IFN-GAMMA IN HUMAN MACROPHAGES

Cyclooxygenase-2 (COX-2) is the inducible enzyme in macrophages respon sible for high output PG production during inflammation and immune res ponses. Although several stimuli are known to regulate COX-2, the mole cular mechanisms modulating its expression by the cytokine network are poorly understood. As IFN-gamma priming is essential for macrophage a ccessory and effector cell functions, we investigated the effect of IF N-gamma on COX-2 expression in U937 human macrophages stimulated with IL-1 beta. A dose- and time-dependent increase in COX-2 mRNA and prote in expression was evoked by IL-1 beta, whereas the levels of COX-1, th e constitutively expressed isoform, remained unaltered, Interestingly, IFN-gamma-primed cells showed 40 to 60% lower levels of COX-2 mRNA, p rotein expression, and PGE(2) production as compared with nonprimed ce lls, IFN-gamma-priming (50-500 U/ml) down-regulated COX-2 expression i n a time- and dose-dependent fashion. Furthermore, IFN-gamma inhibited COX-2 gene transcription in response to IL-1 beta but not to LPS, In contrast, the rate of decay of COX-2 transcripts in nonprimed and prim ed macrophages was similar (t(1/2) = 3.2 h). The dawn-regulatory effec t of IFN-gamma on IL-1 beta-induced COX-2 expression was abrogated wit h cycloheximide, These results highlight a novel mechanism of COX-2 re gulation by IFN-gamma at the transcriptional level, which may affect t he outcome of inflammatory and immune conditions.