Altered interleukin-12 responsiveness in Th1 and Th2 cells is associated with the differential activation of STAT5 and STAT1
Altered interleukin-12 responsiveness in Th1 and Th2 cells is associated with the differential activation of STAT5 and STAT1
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DOI：
10.1182/blood.v91.4.1341
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发表时间：
1998-02-15
期刊：
影响因子：
20.3
通讯作者：
Frank, DA
中科院分区：
文献类型：
--
作者：
Gollob, JA;Murphy, EA;Frank, DA
T细胞对白介素12(IL-12)的反应是通过信号事件介导的，其中包括STAT4的酪氨酸磷酸化。在被诱导分化为Th1或Th2表型的T细胞中，IL-12的反应性和激活STAT4的能力是不同的。在这份报告中，我们证明了在植物血凝素(PHA)激活的人T细胞中，除了STAT4之外，STAT5、STAT1α和STAT1β还被IL-12激活而被酪氨酸磷酸化。为了了解这些STATs的激活如何有助于T细胞IL-12的反应，我们分析了IL-12诱导的T细胞中STAT5和STAT1的激活，这些T细胞被刺激经历Th1或Th2分化。与单独用PHA激活的T细胞相比，IL-12诱导的STAT5和STAT1而不是STAT4的酪氨酸磷酸化在PHA+干扰素-γ(干扰素-γ)激活的T细胞中被增强。与单独用PHA激活的T细胞相比，PHA+干扰素-γ激活的T细胞中IL-12诱导的Stat5 DNA结合也增强，而STAT4 DNA结合不增加。相反，在用PHA+IL-4激活为Th2细胞的T细胞中，IL-12诱导的这些STATS的激活被抑制。干扰素-γ对IL-12信号的增强作用不是干扰素-γ对T细胞的直接作用，而是由抗原提呈细胞产生的IL-12介导的。IL-12对SELECT STATS激活的这种积极的自我调节作用与IL-12引起的T细胞干扰素-伽马产生的增加有关。这些发现表明，STAT5和STAT1的激活可能增强Th1细胞对IL-12的选择性STAT4依赖的功能反应。(C)1998年由美国血液病学会主办。
T-cell activation in response to interleukin-12 (IL-12) is mediated through signaling events that include the tyrosine phosphorylation of STAT4. IL-12 responsiveness and the ability of IL-12 to activate STAT4 is different in T cells induced to differentiate into a Th1 or Th2 phenotype. In this report, we show that STAT5, STAT1 alpha, and STAT1 beta, in addition to STAT4, are tyrosine phosphorylated in response to IL-12 in phytohemagglutinin (PHA)-activated human T cells. To understand how the activation of these STATs contributes to T cell IL-12 responsiveness, we analyzed the IL-12-induced activation of STAT5 and STAT1 in T cells stimulated to undergo Th1 or Th2 differentiation. The IL-12-induced tyrosine phosphorylation of STAT5 and STAT1, but not STAT4, is augmented in T cells activated into Th1 cells with PHA + interferon-gamma (IFN-gamma) compared with T cells activated with PHA alone. STAT5 DNA binding induced by IL-12 is also augmented in T cells activated with PHA + IFN-gamma compared with T cells activated with PHA alone, whereas STAT4 DNA binding is not increased. In contrast, the IL-12-induced activation of these STATs is inhibited in T cells activated into Th2 cells with PHA + IL-4. The enhancement of IL-12 signaling by IFN-gamma is not a direct effect of IFN-gamma on T cells, but rather is mediated by IL-12 that is produced by antigen-presenting cells in response to IFN-gamma. This positive autoregulatory effect of IL-12 on the activation of select STATs correlates with an increase in T-cell IFN-gamma production in response to IL-12. These findings suggest that the activation of STAT5 and STAT1 may augment select STAT4-dependent functional responses to IL-12 in Th1 cells. (C) 1998 by The American Society of Hematology.