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

Cellular Signalling
José L JimenezM Fresno

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.

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Citations

Dec 13, 2006·Expert Opinion on Investigational Drugs·Claus Kroegel, Martin Foerster
Oct 20, 2007·Biochimica Et Biophysica Acta·Thomas KleinMartin Kömhoff
Jun 20, 2012·Innate Immunity·Alexander PuzikChristoph Härtel
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May 4, 2021·Frontiers in Cell and Developmental Biology·Paul M EpsteinStefan Brocke

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