Cyclooxygenase-independent inhibitory effects on T cell activation of novel 4,5-dihydro-3 trifluoromethyl pyrazole cyclooxygenase-2 inhibitors

被引:22
作者
Iniguez, Miguel A. [1 ]
Punzon, Carmen [1 ]
Cacheiro-Llaguno, Cristina [1 ]
Diaz-Munoz, Manuel D. [1 ]
Duque, Javier [1 ]
Cuberes, Rosa [2 ]
Alvarez, Ines [2 ]
Andres, Eva M. [2 ]
Buxens, Jordi [2 ]
Buschmann, Helmut [2 ]
Vela, Jose M. [2 ]
Fresno, Manuel [1 ]
机构
[1] Univ Autonoma Madrid, Ctr Biol Mol Severo Ochoa CSIC UAM, Dept Biol Mol, E-28049 Madrid, Spain
[2] Labs Esteve, Barcelona 08041, Spain
关键词
Cyclooxygenase-2; NSAIDs; NFAT; T lymphocytes; Prostaglandins; Transcriptional regulation; NF-KAPPA-B; NONSTEROIDAL ANTIINFLAMMATORY DRUGS; TRANSCRIPTIONAL ACTIVITY; NUCLEAR FACTOR; PROSTAGLANDIN SYNTHESIS; SODIUM-SALICYLATE; IMMUNE-RESPONSES; ANTIGEN RECEPTOR; IN-VITRO; KINASE;
D O I
10.1016/j.intimp.2010.07.013
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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)-alpha and Interferon (IFN)-gamma 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)-kappa B 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. (C) 2010 Elsevier B.V. All rights reserved.
引用
收藏
页码:1295 / 1304
页数:10
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