IFN-γ suppresses STAT6 phosphorylation by inhibiting its recruitment to the IL-4 receptor
IFN-γ suppresses STAT6 phosphorylation by inhibiting its recruitment to the IL-4 receptor
复制标题
DOI：
10.4049/jimmunol.174.3.1332
复制
发表时间：
2005-02-01
影响因子：
4.4
通讯作者：
Huang, H
中科院分区：
文献类型：
--
作者：
Huang, Z;Xin, JP;Huang, H
极化的Th 1细胞表现出稳定的表型：它们变得对IL-4刺激不敏感并失去产生IL-4的潜力。在此之前，我们报道了IFN-γ在稳定Th 1表型中起着关键作用。然而，IFN-γ稳定Th 1表型的机制尚不清楚。在这项研究中，我们比较了野生型（WT）和IFN-γ受体敲除（IFNGR（-/-））Th 1细胞中STAT 6的磷酸化。我们发现在分化的WT Th 1细胞中STAT 6磷酸化显著减少，但在分化的IFNGR（-/-）Th 1细胞中没有。在分化的WT Th 1细胞中STAT 6磷酸化的损伤不是由于缺乏IL-4 R表达或磷酸化。Jak 1和Jak 3表达和磷酸化在两种细胞类型中相当。在两种细胞类型中未观察到细胞因子信号转导抑制因子1（SOCS 1）、SOCS 3或SOCS 5的差异表达。此外，含Src同源性2的磷酸酶突变不影响IL-4诱导的来自活的飞蛾（me（v）/me（v））小鼠的分化的Th 1细胞中的STAT 6磷酸化。这些结果使我们专注于一种新的机制。通过pulldown实验，我们观察到WT Th 1细胞中的STAT 6与磷酸化IL-4 R/GST融合蛋白的结合比IFNGR（-/-）Th 1细胞中的弱。我们的研究结果表明，IFN-γ可以抑制STAT 6的磷酸化，抑制其募集IL-4 R。
Polarized Th1 cells show a stable phenotype: they become insensitive to IL-4 stimulation and lose the potential to produce IL-4. Previously, we reported that IFN-gamma played a critical role in stabilizing Th1 phenotype. However, the mechanism by which IFN-gamma stabilizes Th1 phenotype is not clear. In this study, we compared STAT6 phosphorylation in wild-type (WT) and IFN-gamma receptor knockout (IFNGR(-/-)) Th1 cells. We found a striking diminution of STAT6 phosphorylation in differentiated WT Th1 cells, but not in differentiated IFNGR(-/-) Th1 cells. The impairment of STAT6 phosphorylation in differentiated WT Th1 cells was not due to a lack of IL-4R expression or phosphorylation. Jak1 and Jak3 expression and phosphorylation were comparable in both cell types. No differential expression of suppressor of cytokine signaling 1 (SOCS1), SOCS3, or SOCS5 was observed in the two cell types. In addition, Src homology 2-containing phosphatase mutation did not affect IL-4-induced STAT6 phosphorylation in differentiated Th1 cells derived from viable motheaten (me(v)/me(v)) mice. These results led us to focus on a novel mechanism. By using a pulldown assay, we observed that STAT6 in WT Th1 cells bound less effectively to the phosphorylated IL-4R/GST fusion protein than that in IFNGR(-/-) Th1 cells. Our results suggest that IFN-gamma may suppress phosphorylation of STAT6 by inhibiting its recruitment to the IL-4R.