Cyclooxygenase-2 expression by nonsteroidal anti-inflammatory drugs in human airway smooth muscle cells: role of peroxisome proliferator-activated receptors.
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-1beta-induced COX-2 expression in human airway smooth muscle (HASM) cells. These effects were not reversed by exogenous PGE(2), suggesting that they are prostanoid-independent. Indeed, PGE(2) also induced and enhanced IL-1beta-induced COX-2 expression. Peroxisome proliferator-activated receptor (PPAR) alpha and PPARgamma (not PPARbeta) were expressed in HASM cells. PPARgamma activators ciglitizone (Cig) and 15-Deoxy-Delta(12,14)-PGJ(2) (15d-PGJ(2)), but not the PPARalpha activator WY-14643, mimicked the effect of NSAIDs on COX-2 expression. Treatment with Flur, NS-398, Cig, and 15d-PGJ(2) alone, but not Indo and WY-14643, elevated COX activity; however, neither enhanced IL-1beta-induced COX activity. Pretreatment with dexamethasone suppressed COX-2 expression, PGE(2) release, and COX activity induced by NS-398, Cig, IL-1beta, alone or in combination. Unlike IL-1beta, NS-398 and Cig did not cause NF-kappaB (p65) nuclear translocation, nor did they further enhance IL-1beta-induced NF-kappaB translocation, but they stimulated PPARgamma translocation. Indo, NS-398, Flur, and 15d-PGJ(2), 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-1beta, 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 PPARgamma activation, and provide the first direct evidence that the PPRE in the promoter is required for NSAID-induced COX-2 expression.
Pang
Linhua
L
Division of Respiratory Medicine, City Hospital, University of Nottingham, United Kingdom. linhua.pang@nottingham.ac.uk
Nie
Mei
M
Corbett
Lisa
L
Knox
Alan J
AJ
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D051546:Cyclooxygenase 2; D003907:Dexamethasone / Q000494:pharmacology; D015232:Dinoprostone / Q000096:biosynthesis / Q000378:metabolism; D005480:Flurbiprofen / Q000494:pharmacology; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000166:cytology / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D008565:Membrane Proteins; D009130:Muscle, Smooth / Q000166:cytology / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009578:Nitrobenzenes / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011448:Prostaglandin Antagonists / Q000494:pharmacology; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D011453:Prostaglandins / Q000502:physiology; D021381:Protein Transport / Q000187:drug effects; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D020218:Response Elements / Q000235:genetics; D013449:Sulfonamides / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015533:Transcriptional Activation / Q000187:drug effects
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D000276:Adjuvants, Immunologic; D000894:Anti-Inflammatory Agents, Non-Steroidal; D007527:Isoenzymes; D008565:Membrane Proteins; D016328:NF-kappa B; D009578:Nitrobenzenes; D011448:Prostaglandin Antagonists; D011453:Prostaglandins; D018160:Receptors, Cytoplasmic and Nuclear; D013449:Sulfonamides; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D005480:Flurbiprofen; D003907:Dexamethasone; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone; D015230:Prostaglandin D2; C039671:ciglitazone; D007213:Indomethacin