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A Chromatin Immunoprecipitation Assay to Identify Novel NFAT2 Target Genes in Chronic Lymphocytic Leukemia
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Effect of phosphodiesterase 4 inhibitors on NFAT-dependent cyclooxygenase-2 expression in human T lymphocytes

José L Jimenez1, Miguel A Iñiguez, M Angeles Muñoz-Fernández

  • 1Laboratorio de Inmunología, Hospital Universitario Gregorio Marañón, C/ Doctor Esquerdo 46, 28007 Madrid, Spain.

Cellular Signalling
|September 24, 2004
PubMed

Insights

Phosphodiesterase (PDE)-4 inhibitors block cyclooxygenase-2 (COX-2) induction in T cells by preventing nuclear factor of activated T cells (NFAT) binding to DNA. This mechanism explains the anti-inflammatory effects of PDE4 inhibitors.

Area of Science:

  • Immunology
  • Molecular Biology
  • Pharmacology

Background:

  • Cyclooxygenase-2 (COX-2) induction in T cells is an early event in inflammation.
  • Phosphodiesterase (PDE)-4 inhibitors are known for their anti-inflammatory properties.

Purpose of the Study:

  • To investigate the mechanism by which PDE4 inhibitors block COX-2 induction in activated T cells.
  • To elucidate the role of nuclear factor of activated T cells (NFAT) in this process.

Main Methods:

  • T cell activation and stimulation.
  • Analysis of COX-2 mRNA and protein levels.
  • Assessment of NFAT DNA binding and transactivation activity.
  • Pharmacological inhibition studies using PDE4 inhibitors and cAMP/PKA modulators.

Main Results:

  • PDE4 inhibitors effectively blocked COX-2 induction and prostaglandin synthesis in activated T cells.
  • Inhibition occurred at the transcriptional level, specifically involving NFAT-responsive elements in the COX-2 promoter.
  • PDE4 inhibitors prevented NFAT binding to DNA and its transactivation function, independent of nuclear translocation.
  • These effects were not mediated by the cAMP-dependent protein kinase (PKA) pathway.

Conclusions:

  • PDE4 inhibitors suppress COX-2 expression by interfering with NFAT-mediated transcriptional activation.
  • This mechanism contributes to the anti-inflammatory actions of PDE4 inhibitors by blocking pro-inflammatory gene induction.

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