Early target genes of IL-12 and STAT4 signaling in Th cells
Early target genes of IL-12 and STAT4 signaling in Th cells
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DOI：
10.4049/jimmunol.172.11.6775
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发表时间：
2004-06-01
影响因子：
4.4
通讯作者：
Lahesmaa, R
中科院分区：
文献类型：
--
作者：
Lund, RJ;Chen, Z;Lahesmaa, R
通过 STAT4 的 IL-12 信号传导对于诱导 IFN-γ 产生的最佳水平和 Th1 细胞的定型至关重要。控制 IL-12 和 STAT4 信号传导如何诱导 Th1 分化的分子机制尚不清楚。为了确定 IL-12 和 STAT4 信号传导的早期靶基因，使用寡核苷酸阵列比较了野生型和 STAT4 敲除小鼠 Th 细胞在早期 Th1 分化过程中的基因表达谱。根据结果，20 个基因以 IL-12 和 STAT4 依赖性方式受到调节。重要的是，Ifngamma 显然是 IL-12 以 STAT4 依赖性方式诱导的第一个基因。 STAT4 敲除细胞中的大多数其他基因表达缺陷是在 Th1 极化 48 小时后观察到的。除了 STAT4 介导的 IL-12 信号传导之外，在 Th1 诱导反应中立即观察到许多基因的不依赖于 STAT4 的诱导。这种诱导至少部分是由独立于 STAT4 的 IFN-gamma 驱动的。重要的是，将外源IFN-γ添加到STAT4敲除细胞的Th1细胞培养物中可以恢复IFN-γ产生的缺陷，进一步证明IFN-γ在早期Th1分化中的关键作用。
IL-12 signaling through STAT4 is essential for induction of optimal levels of IFN-gamma production and commitment of Th1 cells. The molecular mechanism that controls how IL-12 and STAT4 signaling induces Th1 differentiation is poorly described. To identify the early target genes of IL-12 and STAT4 signaling, oligonucleotide arrays were used to compare the gene expression profiles of wild-type and STAT4-knockout murine Th cells during the early Th1 differentiation. According to the results, 20 genes were regulated in an IL-12- and STAT4-dependent manner. Importantly, Ifngamma was clearly the first gene induced by IL-12 in a STAT4-dependent manner. Most of the other defects in gene expression in STAT4-knockout cells were seen after 48 h of Th1 polarization. In addition to IL-12 signaling mediated by STAT4, STAT4-independent induction of a number of genes was observed immediately in response to Th1 induction. This induction was at least in part driven by IFN-gamma independently of STAT4. Importantly, addition of exogenous IFN-gamma into Th1 cell cultures of STAT4-knockout cells restored the defect in IFN-gamma production further demonstrating the critical role of IFN-gamma in early Th1 differentiation.