کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
2541229 | 1122647 | 2010 | 10 صفحه PDF | دانلود رایگان |
![عکس صفحه اول مقاله: Cyclooxygenase-independent inhibitory effects on T cell activation of novel 4,5-dihydro-3 trifluoromethyl pyrazole cyclooxygenase-2 inhibitors Cyclooxygenase-independent inhibitory effects on T cell activation of novel 4,5-dihydro-3 trifluoromethyl pyrazole cyclooxygenase-2 inhibitors](/preview/png/2541229.png)
Anti-inflammatory efficacy of non-steroidal anti-inflammatory drugs (NSAIDs) has been related to their properties as inhibitors of cyclooxygenase (COX)-mediated prostaglandin (PG) synthesis. However, recent studies have suggested that variations of the in vivo anti-inflammatory actions among different NSAIDs could not be solely explained by COX inhibition. Here, we have analyzed the effects on T cell activation of novel 4,5-dihydro-3 trifluoromethyl pyrazole anti-inflammatory drugs with different potencies as COX-2 inhibitors, namely E-6087, E-6232, E-6231, E-6036 and E-6259 as well as the chemically related COX-2 inhibitor Celecoxib. These drugs inhibited mitogen-mediated T cell proliferation as well as Interleukin (IL)-2, tumor necrosis factor (TNF)-α and Interferon (IFN)-γ synthesis by activated T cells, independently of their ability to inhibit COX-2 enzymatic activity. Immunosuppressive effects of these drugs seem to be due to their interference on transcription factor activation as induced transcription from Nuclear Factor (NF)-κB and Nuclear Factor of Activated T cells (NFAT)-dependent enhancers was inhibited in a dose-dependent manner, being the latter effect the most sensitive to the action of those compounds. Both NFAT dephosphorylation, required for its nuclear translocation, as well as transcriptional activity of a GAL4-NFAT chimera were diminished in the presence of these compounds. These findings provide new insights into the molecular mechanisms involved in the immunomodulatory and anti-inflammatory actions of NSAIDs, which may have important implications in anti-inflammatory therapy, through inhibition of NFAT.
Research Highlights
► Novel diarylpyrazole derivatives show different potencies as COX-2 inhibitors.
► These compounds display COX–independent immunosuppressant effects.
► They are able to inhibit T lymphocyte proliferation and production of cytokines.
► These NSAIDs interfere with activation of transcription factors as NFAT and NFκB.
Journal: International Immunopharmacology - Volume 10, Issue 10, October 2010, Pages 1295–1304