Kaplan M H, Daniel C, Schindler U, Grusby M J
Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts 02115, USA.
Mol Cell Biol. 1998 Apr;18(4):1996-2003. doi: 10.1128/MCB.18.4.1996.
The proliferation of lymphocytes in response to cytokine stimulation is essential for a variety of immune responses. Recent studies with signal transducer and activator of transcription 6 (Stat6)-deficient mice have demonstrated that this protein is required for the normal proliferation of lymphocytes in response to interleukin-4 (IL-4). In this report, we show that the impaired IL-4-induced proliferative response of Stat6-deficient lymphocytes is not due to an inability to activate alternate signaling pathways, such as those involving insulin receptor substrates, or to a failure to upregulate IL-4 receptor levels. Cell cycle analysis showed that the percentage of Stat6-deficient lymphocytes that transit from the G1 to the S phase of the cell cycle following IL-4 stimulation is lower than that of control lymphocytes. Although the regulation of many genes involved in the control of cytokine-induced proliferation is normal in Stat6-deficient lymphocytes, protein levels of the cdk inhibitor p27Kip1 were found to be markedly dysregulated. p27Kip1 is expressed at significantly higher levels in Stat6-deficient lymphocytes than in control cells following IL-4 stimulation. The higher level of p27Kip1 expression seen in IL-4-stimulated Stat6-deficient lymphocytes correlates with decreased cdk2-associated kinase activity and is the result of the increased accumulation of protein rather than altered mRNA expression. Similarly, higher levels of p27Kip1 protein expression are also seen following IL-12 stimulation of Stat4-deficient lymphocytes than are seen following stimulation of control cells. These data suggest that Stat proteins may control the cytokine-induced proliferative response of activated T cells by regulating the expression of cell cycle inhibitors so that cyclin-cdk complexes may function to promote transition from the G1 to the S phase of the cell cycle.
淋巴细胞对细胞因子刺激的增殖对于多种免疫反应至关重要。最近对信号转导及转录激活因子6（Stat6）缺陷小鼠的研究表明，该蛋白是淋巴细胞对白细胞介素-4（IL-4）正常增殖所必需的。在本报告中，我们表明Stat6缺陷淋巴细胞中IL-4诱导的增殖反应受损并非由于无法激活替代信号通路，如涉及胰岛素受体底物的信号通路，也不是由于未能上调IL-4受体水平。细胞周期分析表明，IL-4刺激后从细胞周期的G1期过渡到S期的Stat6缺陷淋巴细胞百分比低于对照淋巴细胞。尽管Stat6缺陷淋巴细胞中许多参与细胞因子诱导增殖控制的基因调控正常，但发现细胞周期蛋白依赖性激酶抑制剂p27Kip1的蛋白水平明显失调。在IL-4刺激后，Stat6缺陷淋巴细胞中p27Kip1的表达水平明显高于对照细胞。在IL-4刺激的Stat6缺陷淋巴细胞中看到的较高水平的p27Kip1表达与cdk2相关激酶活性降低相关，并且是蛋白积累增加的结果，而不是mRNA表达改变的结果。同样，在IL-12刺激Stat4缺陷淋巴细胞后，也观察到p27Kip1蛋白表达水平高于对照细胞刺激后。这些数据表明，Stat蛋白可能通过调节细胞周期抑制剂的表达来控制活化T细胞的细胞因子诱导增殖反应，从而使细胞周期蛋白-cdk复合物发挥作用，促进细胞周期从G1期过渡到S期。
