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Negatively Regulates T-bet Transcription Through Suppression of p38 Mitogen-Activated Protein Kinase Activation1
* Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT 84132; and
Geriatric Research, Education and Clinical Center, Veterans Affairs Medical Center, Salt Lake City, UT 84112
Expression of the nuclear hormone receptor peroxisome proliferator-activated receptor 
(PPAR) in resting lymphocytes was recently established, although the physiologic role(s) played by this nuclear hormone receptor in these cell types remains unresolved. In this study, we used CD4+ T cells isolated from PPAR-/- and wild-type mice, as well as cell lines that constitutively express PPAR, in experiments designed to evaluate the role of this hormone receptor in the regulation of T cell function. We report that activated CD4+ T cells lacking PPAR produce increased levels of IFN-
, but significantly lower levels of IL-2 when compared with activated wild-type CD4+ T cells. Furthermore, we demonstrate that PPAR regulates the expression of these cytokines by CD4+ T cells in part, through its ability to negatively regulate the transcription of T-bet. The induction of T-bet expression in CD4+ T cells was determined to be positively influenced by p38 mitogen-activated protein (MAP) kinase activation, and the presence of unliganded PPAR effectively suppressed the phosphorylation of p38 MAP kinase. The activation of PPAR with highly specific ligands relaxed its capacity to suppress p38 MAP kinase phosphorylation and promoted T-bet expression. These results demonstrate a novel DNA-binding independent and agonist-controlled regulatory influence by the nuclear hormone receptor PPAR.
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