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The Journal of Immunology, 2003, 170: 1043-1051.
Copyright © 2003 by The American Association of Immunologists

Cyclooxygenase-2 Expression by Nonsteroidal Anti-inflammatory Drugs in Human Airway Smooth Muscle Cells: Role of Peroxisome Proliferator-Activated Receptors1

Linhua Pang2, Mei Nie, Lisa Corbett and Alan J. Knox

Division of Respiratory Medicine, City Hospital, University of Nottingham, Nottingham, United Kingdom

Nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to modulate cyclooxygenase (COX)-2 expression, but the mechanisms involved are controversial and may be cell specific. We show in this study that indomethacin (Indo), flurbiprofen (Flur), and the selective COX-2 inhibitor NS-398 induced COX-2 expression and markedly enhanced IL-1{beta}-induced COX-2 expression in human airway smooth muscle (HASM) cells. These effects were not reversed by exogenous PGE2, suggesting that they are prostanoid-independent. Indeed, PGE2 also induced and enhanced IL-1{beta}-induced COX-2 expression. Peroxisome proliferator-activated receptor (PPAR) {alpha} and PPAR{gamma} (not PPAR{beta}) were expressed in HASM cells. PPAR{gamma} activators ciglitizone (Cig) and 15-Deoxy-{Delta}12,14-PGJ2 (15d-PGJ2), but not the PPAR{alpha} activator WY-14643, mimicked the effect of NSAIDs on COX-2 expression. Treatment with Flur, NS-398, Cig, and 15d-PGJ2 alone, but not Indo and WY-14643, elevated COX activity; however, neither enhanced IL-1{beta}-induced COX activity. Pretreatment with dexamethasone suppressed COX-2 expression, PGE2 release, and COX activity induced by NS-398, Cig, IL-1{beta}, alone or in combination. Unlike IL-1{beta}, NS-398 and Cig did not cause NF-{kappa}B (p65) nuclear translocation, nor did they further enhance IL-1{beta}-induced NF-{kappa}B translocation, but they stimulated PPAR{gamma} translocation. Indo, NS-398, Flur, and 15d-PGJ2, but not WY-14643, induced transcriptional activity of a COX-2 reporter construct containing the peroxisome proliferator response element (PPRE) on their own and enhanced the effect of IL-1{beta}, but had no effect on a COX-2 reporter construct lacking the PPRE. The results suggest that COX-2 expression by NSAIDs is biologically functional, prostanoid-independent, and involves PPAR{gamma} activation, and provide the first direct evidence that the PPRE in the promoter is required for NSAID-induced COX-2 expression.


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