Kusaba Hitoshi, Ghosh Paritosh, Derin Rachel, Buchholz Meredith, Sasaki Carl, Madara Karen, Longo Dan L
Lymphocyte Cell Biology Unit, Laboratory of Immunology, Gerontology Research Center, NIA, National Institutes of Health, Baltimore, Maryland 21224, USA.
J Biol Chem. 2005 Jan 14;280(2):1037-43. doi: 10.1074/jbc.M405204200. Epub 2004 Nov 1.
Depending on the type of external signals, T cells can initiate multiple intracellular signaling pathways that can be broadly classified into two groups based on their sensitivity to the immunosuppressive drug cyclosporin A (CsA). Interleukin (IL)-12-mediated interferon (IFN)-gamma production by activated T cells has been shown to be CsA-insensitive. In this report, we demonstrate that the IL-12-induced CsA-resistant pathway of IFN-gamma production is sensitive to rapamycin. Rapamycin treatment resulted in the aberrant recruitment of Stat3, Stat4, and phospho-c-Jun to the genomic promoter region resulting in decreased IFN-gamma transcription. IL-12-induced phosphorylation of Stat3 on Ser-727 was affected by rapamycin, which may be due to the effect of rapamycin on the IL-12-induced interaction between mammalian target of rapamycin (mTOR) and Stat3. In accordance with this, reduction in the mTOR protein level by small interfering RNA resulted in suppression of Stat3 phosphorylation and decreased production of IFN-gamma after IL-12 stimulation. These results suggest that mTOR may play a major role in IL-12-induced IFN-gamma production by activated T cells.
根据外部信号的类型，T细胞可启动多种细胞内信号通路，根据其对免疫抑制药物环孢素A（CsA）的敏感性，这些信号通路可大致分为两组。活化的T细胞通过白细胞介素（IL）-12介导产生干扰素（IFN）-γ，已被证明对CsA不敏感。在本报告中，我们证明IL-12诱导的IFN-γ产生的CsA抗性途径对雷帕霉素敏感。雷帕霉素处理导致Stat3、Stat4和磷酸化c-Jun异常募集到基因组启动子区域，导致IFN-γ转录减少。雷帕霉素影响IL-12诱导的Stat3在Ser-727位点的磷酸化，这可能是由于雷帕霉素对IL-12诱导的雷帕霉素哺乳动物靶标（mTOR）与Stat3之间相互作用的影响。与此一致，小干扰RNA降低mTOR蛋白水平导致Stat3磷酸化受到抑制，IL-12刺激后IFN-γ产生减少。这些结果表明，mTOR可能在活化的T细胞通过IL-12诱导产生IFN-γ的过程中起主要作用。
