Effect of phosphodiesterase 4 inhibitors on NFAT-dependent cyclooxygenase-2 expression in human T lymphocytes
Autor: | Manuel Fresno, Jose L. Jimenez, Miguel A. Iñiguez, M. Ángeles Muñoz-Fernández |
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Rok vydání: | 2004 |
Předmět: |
Transcriptional Activation
medicine.medical_specialty Indoles T-Lymphocytes T cell Immunoblotting Carbazoles Biology Transfection CREB Jurkat Cells Transactivation chemistry.chemical_compound Internal medicine medicine Humans Pyrroles RNA Messenger Enzyme Inhibitors Luciferases Promoter Regions Genetic Sulfonamides Forskolin Dose-Response Relationship Drug NFATC Transcription Factors Colforsin T-cell receptor Membrane Proteins Nuclear Proteins Phosphodiesterase NFAT DNA Cell Biology Isoquinolines Cyclic Nucleotide Phosphodiesterases Type 4 Cell biology DNA-Binding Proteins medicine.anatomical_structure Endocrinology chemistry 3' 5'-Cyclic-AMP Phosphodiesterases Cyclooxygenase 2 Prostaglandin-Endoperoxide Synthases biology.protein Cyclooxygenase Rolipram Plasmids Protein Binding Transcription Factors |
Zdroj: | Cellular Signalling. 16:1363-1373 |
ISSN: | 0898-6568 |
Popis: | Transcriptional induction of cyclooxygenase-2 (COX-2) occurs early after T cell receptor triggering and has functional implications in inflammation. Here, we show that phosphodiesterase (PDE)-4 inhibitors block COX-2 induction and prostaglandin synthesis in activated T cells. COX-2 inhibition by PDE4 inhibitors occurs mainly at the transcriptional level. Two response elements for the nuclear factor of activated T cells (NFAT) in the COX-2 promoter were required for inhibition by these drugs. PDE4 inhibitors did not affect NFAT nuclear translocation upon T cell activation; rather they prevented NFAT binding to DNA and induction of the transactivation function of GAL4-NFAT. These effects seem to be cAMP/PKA independent as they were not mimicked by the permeable analog dBcAMP or by forskolin, neither can be reverted by the PKA inhibitors H89 or KT-5720. These results may explain some of the anti-inflammatory properties of PDE4 inhibitors through the blockade of NFAT-mediated transactivation of pro-inflammatory genes such as COX-2. |
Databáze: | OpenAIRE |
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