1. Cyclooxygenase-independent inhibitory effects on T cell activation of novel 4,5-dihydro-3 trifluoromethyl pyrazole cyclooxygenase-2 inhibitors.
- Author
-
Iñiguez MA, Punzón C, Cacheiro-Llaguno C, Díaz-Muñoz MD, Duque J, Cuberes R, Alvarez I, Andrés EM, Buxens J, Buschmann H, Vela JM, and Fresno M
- Subjects
- Animals, Anti-Inflammatory Agents, Non-Steroidal chemistry, Exudates and Transudates chemistry, Gastric Mucosa drug effects, Gene Expression Regulation physiology, Humans, Inflammation metabolism, Jurkat Cells, Molecular Structure, NF-kappa B metabolism, NFATC Transcription Factors metabolism, Pyrazoles chemistry, Rats, Anti-Inflammatory Agents, Non-Steroidal pharmacology, Cyclooxygenase 2 Inhibitors pharmacology, Lymphocyte Activation drug effects, Pyrazoles pharmacology, T-Lymphocytes drug effects, T-Lymphocytes physiology
- Abstract
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., (Copyright © 2010 Elsevier B.V. All rights reserved.)
- Published
- 2010
- Full Text
- View/download PDF