Molecular mechanism of interleukin-2-induced mucosal homeostasis.
Molecular mechanism of interleukin-2-induced mucosal homeostasis.
复制标题
DOI：
10.1152/ajpcell.00316.2011
复制
发表时间：
2012-03
期刊：
影响因子：
--
通讯作者：
Jayshree Mishra;C. Waters;Narendra Kumar
中科院分区：
文献类型：
--
作者：
Jayshree Mishra;C. Waters;Narendra Kumar
炎症性肠病（IBD）患者粘膜内层的持续损伤促进肠道微生物移位至粘膜下免疫细胞，导致慢性炎症。以前，我们证明了Jak 3在IL-2诱导的肠上皮细胞（IEC）迁移中的作用，这是肠创伤修复过程中的早期事件之一。在这项研究中，我们表明，IL-2也发挥了作用，通过IEC增殖和细胞死亡的浓度依赖性调节IEC稳态。在低浓度（≤50 U/ml）时，IL-2促进细胞增殖;在高浓度（100 U/ml）时，IL-2促进细胞凋亡。IL-2的激活导致Jak 3和p52 ShcA之间的酪氨酸磷酸化依赖性相互作用仅在较低浓度下。磷酸酶SHP 1去磷酸化IL-2诱导的磷酸化p52 ShcA。高浓度的IL-2降低了Jak 3和p52 ShcA的磷酸化，破坏了它们之间的相互作用，将Jak 3重新分配到细胞核中，并诱导IEC细胞凋亡。IL-2还诱导剂量依赖性p52 shcA上调和jak 3-mRNA下调。组成性过表达和miR-shRNA介导的敲低研究表明，Jak 3和p52 ShcA的表达是IL-2诱导IEC增殖所必需的。多西环素调控的sh-RNA表达表明，IL-2诱导的jak 3-mRNA的下调是导致IEC中IL-2诱导的凋亡增加的原因。总的来说，这些数据证明了一种新的机制，IL-2诱导的粘膜稳态通过翻译后和转录调控Jak 3和p52 ShcA。
Sustained damage to the mucosal lining in patients with inflammatory bowel disease (IBD) facilitates translocation of intestinal microbes to submucosal immune cells leading to chronic inflammation. Previously, we demonstrated the role of Jak3 in IL-2-induced intestinal epithelial cell (IEC) migration, one of the early events during intestinal wound repair. In this study, we demonstrate that IL-2 also plays a role in IEC homeostasis through concentration-dependent regulation of IEC proliferation and cell death. At lower concentrations (≤50 U/ml), IL-2 promoted proliferation, while at higher concentrations (100 U/ml), it promoted apoptosis. Activation by IL-2 led to tyrosine phosphorylation-dependent interactions between Jak3 and p52ShcA only at lower concentrations. Phosphatase SHP1 dephosphorylated IL-2-induced phosphorylated p52ShcA. Higher concentrations of IL-2 decreased the phosphorylation of Jak3 and p52ShcA, disrupted their interactions, redistributed Jak3 to the nucleus, and induced apoptosis in IEC. IL-2 also induced dose-dependent upregulation of p52shcA and downregulation of jak3-mRNA. Constitutive overexpression and mir-shRNA-mediated knockdown studies showed that expression of both Jak3 and p52ShcA were necessary for IL-2-induced proliferation of IEC. Doxycycline-regulated sh-RNA expression demonstrated that IL-2-induced downregulation of jak3-mRNA was responsible for higher IL-2-induced apoptosis in IEC. Collectively, these data demonstrate a novel mechanism of IL-2-induced mucosal homeostasis through posttranslational and transcriptional regulation of Jak3 and p52ShcA.