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Cyclooxygenase-2 Expression by Nonsteroidal Anti-inflammatory Drugs in Human Airway Smooth Muscle Cells: Role of Peroxisome Proliferator-Activated Receptors
| Content Provider | Scilit |
|---|---|
| Author | Pang, Linhua Nie, Mei Corbett, Lisa Knox, Alan J. |
| Copyright Year | 2003 |
| Abstract | 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-1β-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-1β-induced COX-2 expression. Peroxisome proliferator-activated receptor (PPAR) α and PPARγ (not PPARβ) were expressed in HASM cells. PPARγ activators ciglitizone (Cig) and 15-Deoxy-Δ^{12,14}$-PGJ_{2}$ $(15d-PGJ_{2}$), but not the PPARα 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-1β-induced COX activity. Pretreatment with dexamethasone suppressed COX-2 expression, $PGE_{2}$ release, and COX activity induced by NS-398, Cig, IL-1β, alone or in combination. Unlike IL-1β, NS-398 and Cig did not cause NF-κB (p65) nuclear translocation, nor did they further enhance IL-1β-induced NF-κB translocation, but they stimulated PPARγ 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-1β, 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 PPARγ activation, and provide the first direct evidence that the PPRE in the promoter is required for NSAID-induced COX-2 expression. |
| Ending Page | 1051 |
| Page Count | 9 |
| Starting Page | 1043 |
| ISSN | 00221767 |
| e-ISSN | 15506606 |
| DOI | 10.4049/jimmunol.170.2.1043 |
| Journal | The Journal of Immunology |
| Issue Number | 2 |
| Volume Number | 170 |
| Language | English |
| Publisher | The American Association of Immunologists |
| Publisher Date | 2003-01-15 |
| Access Restriction | Open |
| Subject Keyword | Prostanoid Independent Peroxisome Proliferator Induced Cox |
| Content Type | Text |
| Resource Type | Article |
| Subject | Immunology and Allergy Immunology |
