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Activation of Human T Lymphocytes Is Inhibited by Peroxisome Proliferator-activated Receptor γ (PPARγ) Agonists

X. Yang,Li Hua Wang,Taosheng Chen,D. Hodge,J. Resau,L. DaSilva,W. Farrar

Published 2000 in Journal of Biological Chemistry

ABSTRACT

T lymphocyte activation is highlighted by the induction of interleukin-2 (IL-2) gene expression, which governs much of the early lymphocyte proliferation responses. Peroxisome proliferator-activated receptor-γ (PPARγ) is a member of the nuclear receptor superfamily of ligand-activated transcription factors. PPARγ mRNA expression was found in human peripheral blood T lymphocytes, raising the possibility of PPARγ involvement in the regulation of T cell function. Here we show that PPARγ ligands, troglitazone and 15-deoxy-Δ12,14 prostaglandin J2, but not PPARα agonist Wy14643, inhibited IL-2 production and phytohemagglutinin-inducible proliferation in human peripheral blood T-cells in a dose-dependent manner. This inhibitory effect on IL-2 was restricted to the PPARγ2-expressing, not the PPARγ-lacking, subpopulation of transfected Jurkat cells. The activated PPARγ physically associates with transcriptional factor NFAT regulating the IL-2 promoter, blocking NFAT DNA binding and transcriptional activity. This interaction with T-cell-specific transcription factors indicates an important immunomodulatory role for PPARγ in T lymphocytes and could suggest a previously unrecognized clinical potential for PPARγ ligands as immunotherapeutic drugs to treat T-cell-mediated diseases by targeting IL-2 gene expression.

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