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首页> 外文期刊>PLoS One >Inhibition of G-Protein βγ Signaling Enhances T Cell Receptor-Stimulated Interleukin 2 Transcription in CD4+ T Helper Cells
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Inhibition of G-Protein βγ Signaling Enhances T Cell Receptor-Stimulated Interleukin 2 Transcription in CD4+ T Helper Cells

机译：抑制G蛋白βγ信号传导增强CD4 + T辅助细胞中T细胞受体刺激的白介素2转录。

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G-protein-coupled receptor (GPCR) signaling modulates the expression of cytokines that are drug targets for immune disorders. However, although GPCRs are common targets for other diseases, there are few GPCR-based pharmaceuticals for inflammation. The purpose of this study was to determine whether targeting G-protein βγ (Gβγ) complexes could provide a useful new approach for modulating interleukin 2 (IL-2) levels in CD4+ T helper cells. Gallein, a small molecule inhibitor of Gβγ, increased levels of T cell receptor (TCR)-stimulated IL-2 mRNA in primary human naïve and memory CD4+ T helper cells and in Jurkat human CD4+ leukemia T cells. Gβ1 and Gβ2 mRNA accounted for 99% of Gβ mRNA, and small interfering RNA (siRNA)-mediated silencing of Gβ1 but not Gβ2 enhanced TCR-stimulated IL-2 mRNA increases. Blocking Gβγ enhanced TCR-stimulated increases in IL-2 transcription without affecting IL-2 mRNA stability. Blocking Gβγ also enhanced TCR-stimulated increases in nuclear localization of nuclear factor of activated T cells 1 (NFAT1), NFAT transcriptional activity, and levels of intracellular Ca2+. Potentiation of IL-2 transcription required continuous Gβγ inhibition during at least two days of TCR stimulation, suggesting that induction or repression of additional signaling proteins during T cell activation and differentiation might be involved. The potentiation of TCR-stimulated IL-2 transcription that results from blocking Gβγ in CD4+ T helper cells could have applications for autoimmune diseases.
机译：G蛋白偶联受体（GPCR）信号调节细胞因子的表达，而细胞因子是免疫疾病的药物靶标。但是，尽管GPCR是其他疾病的常见靶标，但很少有基于GPCR的炎症药物。这项研究的目的是确定靶向G蛋白βγ（Gβγ）的复合物是否可以为调节CD4 + T辅助细胞中白介素2（IL-2）水平提供有用的新方法。 Gallein是Gβγ的一种小分子抑制剂，可在原代人初生和记忆CD4 + T辅助细胞以及Jurkat人CD4 +白血病T细胞中增加T细胞受体（TCR）刺激的IL-2 mRNA水平。 Gβ1和Gβ2mRNA占GβmRNA的> 99％，而小干扰RNA（siRNA）介导的Gβ1沉默却不是Gβ2增强的TCR刺激的IL-2 mRNA升高。阻断Gβγ增强了TCR刺激的IL-2转录增加，但不影响IL-2 mRNA的稳定性。阻断Gβγ还可以增强TCR刺激的活化T细胞1（NFAT1）的核因子的核定位，NFAT转录活性和细胞内Ca2 +的水平。 IL-2转录的增强需要在TCR刺激的至少两天内持续抑制Gβγ，这表明在T细胞活化和分化过程中可能涉及诱导或抑制其他信号蛋白。由阻断CD4 + T辅助细胞中的Gβγ引起的TCR刺激的IL-2转录增强可能适用于自身免疫性疾病。

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