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High output of prostaglandins (PGs) are the hallmark of inflammatory and immune reactions. A rate-limiting step in the production of PGs is the presence of the enzyme cyclooxygenase (COX). COX exists as two isoforms: COX-1 which is constitutively expressed in most cells and COX-2 which is inducible by LPS, proinflammatory cytokines and other stimuli in cells involved in inflammation. The objective of this study was to determine the effect of nonsteroidal antiinflammatory drugs and proinflammatory cytokines on COX-2 expression in human macrophages. COX-2 specific (NS-398) and non-specific (aspirin, indomethacin and naproxen) inhibitors showed no effect on COX mRNA and protein expression induced by LPS. In contrast, the drugs markedly inhibited COX activity as measured by the accumulation of PGE2. The induction of COX-2 mRNA expression by LPS was rapid and sustained. However, LPS only transiently stimulated the transcription of COX-2 gene and activation of the transcription factor NF-kappaB. LPS stimulated the release of IL-1beta and TNF-alpha but these cytokines had no autocrine effect on the transcriptional or post-transcriptional regulation of COX-2. The presence of LPS was essential for the maintenance of high levels of long-lived COX-2 mRNA. As IFN-gamma is a major macrophage activating factor, we determined the role of this cytokine on COX-2 expression induced by exogenous IL-1beta. IFN-gamma-primed macrophages showed significantly lower levels of COX-2 mRNA, protein and PGE2 production compared to non-primed cells. IFN-gamma specifically decreased the transcriptional activation of COX-2 gene by IL-1beta but not by LPS without affecting the rate of mRNA decay. These results demonstrate that sustained production of PGE2 by macrophages in an inflammatory milieu can occur through the stabilization of COX-2 mRNA and revealed a role for IFN-gamma as an anti-inflammatory cytokine counteracting the expression of COX-2. A better understanding of COX-2 regulation will

Bibliography: leaves 211-260 / xvii, 260 leaves ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--University of Adelaide, Dept. of Pathology, 1986