Sustained IL-12 signaling is required for Th1 development
Sustained IL-12 signaling is required for Th1 development
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DOI：
10.4049/jimmunol.172.1.61
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发表时间：
2004-01-01
影响因子：
4.4
通讯作者：
Hilkens, CMU
中科院分区：
文献类型：
--
作者：
Athie-Morales, V;Smits, HH;Hilkens, CMU
STAT4是Th1细胞发育所必需的转录因子，IL-12和干扰素-α都能激活STAT4，但激活的动力学不同。在这项研究中，我们比较了它们推动人类原始Th细胞向Th1表型分化的能力。干扰素-α的Th1极化活性明显弱于IL-12，与STAT4激活动力学的显著差异有关；对IL-12的反应是持续的(48小时)，而对干扰素-α的反应是短暂的(4小时)。持续激活STAT需要IL-12的持续存在。同样，最佳的Th1极化只有在长期暴露于IL-12时才能实现，而不能被瞬时的IL-12脉冲所诱导。此外，细胞因子IL-2通过上调IL-12R的表达来增强持续的IL-12/STAT4反应，并与IL-12协同驱动Th1细胞的发育。另一方面，瞬时的干扰素-α反应不被IL-2延长。干扰素-α诱导干扰素-α-β受体亚单位1下调，使细胞对干扰素-α无效，但不能反式抑制IL-12/STAT4反应。这些数据表明，持续的IL-12信号对于Th1细胞的最佳发育是必不可少的，而干扰素-α对STAT4的瞬时激活可能解释了这种细胞因子对Th1极化能力较差的原因。总而言之，这些数据表明，细胞因子信号的持续时间对于决定生物反应是重要的。
STAT4 is an essential transcription for Th1 cell development IL-12 and IFN-alpha both activate STAT4, but with different kinetics. In this study we compared their capacities to drive differentiation of human naive Th cells toward Th1 phenotype. The Th1-polarizing activity of IFN-alpha was much weaker than that of IL-12, correlating with a marked difference in the kinetics of STAT4 activation; the response to IL-12 was sustained (> 48 h), whereas the response to IFN-alpha was transient (4h). The continuous presence of IL-12 was required for sustained STAT$ activation. Similarly, optimal Th1 polarization was only achieved upon prolonged exposure to IL-12 and could not be induced by a transient IL-12 pulse. Furthermore, the cytokine IL-2 potentiated sustained IL-12/STAT4 responses through up-regulation of IL-12R expression and synergized with IL-12 in driving Th1 cell development. Transient IFN-alpha responses, on the other hand, were not prolonged by IL-2. IFN-alpha treatment induced down-regulation of IFN-alphabeta receptor subunit 1, rendering cells refractory to IFN-alpha, but did not trans-inhibit the IL-12/STAT4 response. These data indicate that sustained IL-12 signaling is essential for optimal Th1 cell development and that transient activation of STAT4 in response to IFN-alpha may explain the poor Th1-polarizing capacity of this cytokine. Collectively these data show that the duration of cytokine signaling is important for determining the biological response.