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
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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