Peroxisome proliferator-activated receptor α negatively regulates T-bet transcription through suppression of p38 mitogen-activated protein kinase activation
Peroxisome proliferator-activated receptor α negatively regulates T-bet transcription through suppression of p38 mitogen-activated protein kinase activation
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DOI：
10.4049/jimmunol.171.1.196
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发表时间：
2003-07-01
影响因子：
4.4
通讯作者：
Daynes, RA
中科院分区：
文献类型：
--
作者：
Jones, DC;Ding, XH;Daynes, RA
最近确定了核激素受体过氧化物酶体增殖物激活受体 α (PPARα) 在静息淋巴细胞中的表达，尽管这种核激素受体在这些细胞类型中所发挥的生理作用仍未解决。在这项研究中，我们使用从 PPARα(-/-) 和野生型小鼠中分离的 CD4(+) T 细胞，以及组成型表达 PPARa 的细胞系，在旨在评估这种激素受体在 T 细胞功能调节中的作用的实验中。我们报道，与激活的野生型CD4(+) T细胞相比，缺乏PPARa的激活的CD4(+) T细胞产生更高水平的IFN-γ，但显着降低IL-2水平。此外，我们证明PPARα通过其负向调节T-bet转录的能力部分地调节CD4(+)T细胞这些细胞因子的表达。 CD4(+) T 细胞中 T-bet 表达的诱导被确定受到 p38 丝裂原激活蛋白 (MAP) 激酶激活的积极影响，并且未配体的 PPARα 的存在有效地抑制了 p38 MAP 激酶的磷酸化。用高度特异性配体激活 PPARα 可以减弱其抑制 p38 MAP 激酶磷酸化的能力并促进 T-bet 表达。这些结果证明了核激素受体 PPARα 具有一种新颖的 DNA 结合独立且激动剂控制的调节影响。
Expression of the nuclear hormone receptor peroxisome proliferator-activated receptor alpha (PPARalpha) 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 PPARalpha(-/-) and wild-type mice, as well as cell lines that constitutively express PPARa, 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 PPARa produce increased levels of IFN-gamma, but significantly lower levels of IL-2 when compared with activated wild-type CD4(+) T cells. Furthermore, we demonstrate that PPARalpha 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 PPARalpha effectively suppressed the phosphorylation of p38 MAP kinase. The activation of PPARalpha 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 PPARalpha.