STAT1 affects lymphocyte survival and proliferation partially independent of its role downstream of IFN-γ
STAT1 affects lymphocyte survival and proliferation partially independent of its role downstream of IFN-γ
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DOI：
10.4049/jimmunol.164.3.1286
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发表时间：
2000-02-01
影响因子：
4.4
通讯作者：
Levy, DE
中科院分区：
文献类型：
--
作者：
Lee, CK;Smith, E;Levy, DE
来自缺乏STAT1的小鼠的淋巴细胞在体外显示出细胞凋亡减少和增殖增强。为了了解STAT1在观察到的细胞凋亡减少中的作用，我们检测了参与细胞存活和/或凋亡的caspase和bcl-2家族基因的水平，与野生型相比，STAT1（-/-）细胞中caspase 1和11的水平降低，这两种酶都参与细胞因子蛋白加工和诱导凋亡。然而，两种小鼠的bcl-2基因水平是相似的，STAT1（-/-）细胞在TCR刺激后也表现出增强的增殖。这种过度增殖不能完全归因于ifn - γ介导的抗增殖的丧失，首先，在来自STAT1（-/-）小鼠的成纤维细胞和前b细胞中也观察到类似的表型，它们不产生ifn - γ，其次，与缺乏ifn - γ基因的细胞或与ifn - γ中和抗体处理的细胞的比较仅部分模仿STAT1（-/-）表型，有趣的是，p27（kip1）的降解动力学，一种CDK抑制剂，与野生型小鼠相比，STAT1（-/-）小鼠受刺激T细胞中CDK2激酶活性和蛋白水平的上调也随之增加。此外，STAT1（-/-）动物更容易患致癌物诱导的胸腺肿瘤，这可能是T细胞生长和/或存活改变的结果。这些结果表明STAT1在淋巴细胞存活和增殖中发挥重要作用，仅部分依赖于ifn - γ信号。
Lymphocytes derived from mice deficient in STAT1 showed reduced apoptosis and enhanced proliferation in vitro. To understand the involvement of STAT1 in the observed reduction in apoptosis, we examined the levels of caspase and bcl-2 family genes that are involved in cell survival and/or apoptosis, The levels of caspase 1 and 11, two enzymes involved in both cytokine protein processing and induction of apoptosis, were reduced in STAT1(-/-) cells compared with wild-type. However, the levels of bcl-2 genes were comparable in both mice, STAT1(-/-) cells also displayed an enhanced proliferation following TCR stimulation. This hyperproliferation could not be ascribed completely to the loss of IFN-gamma-mediated antiproliferation, First, similar phenotypes were also observed in fibroblasts and pre-B cells derived from STAT1(-/-) mice, which do not produce IFN-gamma, Second, comparisons with cells lacking the gene for IFN-gamma or with cells treated with neutralizing Abs to IFN-gamma only partially mimicked the STAT1(-/-) phenotype, Interestingly, the kinetics of degradation of p27(kip1), a CDK inhibitor, following TCR ligation were faster, and, concomitantly, the up-regulation of CDK2 kinase activity and protein levels were increased in stimulated T cells of STAT1(-/-) mice relative to those of wild-type mice. Furthermore, STAT1(-/-) animals were more susceptible to carcinogen-induced thymic tumors, a possible consequence of altered T cell growth and/or survival. These results demonstrate an essential role for STAT1 for lymphocyte survival and proliferation that is only partially dependent on IFN-gamma signaling.