The role of low molecular weight thiols in T lymphocyte proliferation and IL-2 secretion
The role of low molecular weight thiols in T lymphocyte proliferation and IL-2 secretion
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DOI：
10.4049/jimmunol.175.12.7965
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发表时间：
2005-12-15
影响因子：
4.4
通讯作者：
Knudson, CM
中科院分区：
文献类型：
--
作者：
Hadzic, T;Li, L;Knudson, CM
谷胱甘肽（GSH）是一种丰富的细胞内三肽，已被认为是T细胞增殖的重要调节因子。研究了GSH和其他硫醇的药理学调节剂对鼠T细胞信号传导、增殖和细胞内硫醇水平的影响。GSH合成抑制剂L-丁硫氨酸-SR-亚砜亚胺（BSO）可显著降低GSH水平并阻断T细胞增殖，但对细胞活力无显著影响。N-乙酰半胱氨酸显著增强T细胞增殖而不影响GSH水平。用N-乙酰半胱氨酸和BSO共处理T细胞未能恢复GSH水平，但完全恢复了增殖反应。2-ME和L-半胱氨酸也逆转了BSO对T细胞增殖的抑制作用。BSO处理可降低细胞内L-半胱氨酸水平，但用NAC或L-半胱氨酸处理可恢复细胞内L-半胱氨酸水平。然而，2-ME完全逆转BSO抑制增殖，而不增加细胞内半胱氨酸水平。因此，GSH和半胱氨酸都不是限制T细胞增殖的关键因素。需要从游离硫醇还原当量，因为硫醇部分的氧化完全消除了该效应。此外，BSO不改变表面活化标志物的表达，但有效地阻断IL-2和IL-6的分泌。重要的是，外源性IL-2完全克服了BSO诱导的阻滞或T细胞增殖。这些结果表明，T细胞增殖受涉及IL-2的硫醇敏感性途径调节。
Glutathione (GSH) is an abundant intracellular tripeptide that has been implicated as an important regulator of T cell proliferation. The effect of pharmacological regulators of GSH and other thiols on murine T cell signaling, proliferation, and intracellular thiol levels was examined. L-Buthionine-SR-sulfoximine (BSO), an inhibitor of GSH synthesis, markedly reduced GSH levels and blocked T cell proliferation without significant effect on cell viability. N-acetylcysteine markedly enhanced T cell proliferation without affecting GSH levels. Cotreatment of T cells with N-acetyleysteine and BSO failed to restore GSH levels, but completely restored the proliferative response. Both 2-ME and L-cysteine also reversed the BSO inhibition of T cell proliferation. Intracellular L-cysteine levels were reduced with BSO treatment and restored with entreatment with NAC or L-cysteine. However, 2-ME completely reversed the BSO inhibition of proliferation without increasing intracellular cysteine levels. Therefore, neither GSH nor cysteine is singularly critical in limiting T cell proliferation. Reducing equivalents from free thiols were required because oxidation of the thiol moiety completely abolished the effect. Furthermore, BSO did not change the expression of surface activation markers, but effectively blocked IL-2 and IL-6 secretion. Importantly, exogenous IL-2 completely overcame BSO-induced block or T cell proliferation. These results demonstrate that T cell proliferation is regulated by thiol-sensitive pathway involving IL-2.