Effect of phosphodiesterase 4 inhibitors on NFAT-dependent cyclooxygenase-2 expression in human T lymphocytes

Cell Signal. 2004 Dec;16(12):1363-73. doi: 10.1016/j.cellsig.2004.04.002.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3',5'-Cyclic-AMP Phosphodiesterases / antagonists & inhibitors*
  • Carbazoles / pharmacology
  • Colforsin / pharmacology
  • Cyclic Nucleotide Phosphodiesterases, Type 4
  • Cyclooxygenase 2
  • DNA / metabolism
  • DNA-Binding Proteins / metabolism*
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Immunoblotting
  • Indoles / pharmacology
  • Isoquinolines / pharmacology
  • Jurkat Cells
  • Luciferases / metabolism
  • Membrane Proteins
  • NFATC Transcription Factors
  • Nuclear Proteins / metabolism*
  • Plasmids / metabolism
  • Promoter Regions, Genetic
  • Prostaglandin-Endoperoxide Synthases / biosynthesis*
  • Protein Binding
  • Pyrroles / pharmacology
  • RNA, Messenger / metabolism
  • Rolipram / pharmacology
  • Sulfonamides / pharmacology
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / metabolism
  • Transcription Factors / metabolism*
  • Transcriptional Activation
  • Transfection

Substances

  • Carbazoles
  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • Indoles
  • Isoquinolines
  • Membrane Proteins
  • NFATC Transcription Factors
  • Nuclear Proteins
  • Pyrroles
  • RNA, Messenger
  • Sulfonamides
  • Transcription Factors
  • Colforsin
  • KT 5720
  • DNA
  • Luciferases
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • Prostaglandin-Endoperoxide Synthases
  • 3',5'-Cyclic-AMP Phosphodiesterases
  • Cyclic Nucleotide Phosphodiesterases, Type 4
  • Rolipram
  • N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide