Loss of Dok-1 and Dok-2 in mice causes severe experimental colitis accompanied by reduced expression of IL-17A and IL-22.
Loss of Dok-1 and Dok-2 in mice causes severe experimental colitis accompanied by reduced expression of IL-17A and IL-22.
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DOI：
10.1016/j.bbrc.2016.07.079
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发表时间：
2016-09
影响因子：
3.1
通讯作者：
Masazumi Waseda;Sumimasa Arimura;Eri Shimura;S. Nakae;Y. Yamanashi
中科院分区：
文献类型：
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作者：
Masazumi Waseda;Sumimasa Arimura;Eri Shimura;S. Nakae;Y. Yamanashi
适当的免疫反应和黏膜屏障功能是维持肠道稳态所必需的。这种防御系统的缺陷可能导致炎症性疾病，如炎症性肠病。酪氨酸激酶1 （Dok-1）的下游及其最接近的同源物Dok-2在免疫细胞中优先表达，在先天免疫和适应性免疫的多种信号通路的负调控中发挥重要作用。然而，这些蛋白在肠道内稳态中的功能尚不清楚。本研究表明，与Dok-1或Dok-2单敲除和野生型（WT）小鼠相比，Dok-1/ 2双敲除（DKO）小鼠对葡聚糖硫酸钠（DSS）诱导的结肠炎高度敏感。此外，与WT对照组相比，dss处理的Dok-1/-2 DKO小鼠结肠组织损伤增加，上皮细胞增殖减少，这表明Dok-1/-2 DKO小鼠在肠上皮病变修复方面存在缺陷。此外，与WT小鼠相比，dss处理的Dok-1/ 2 DKO小鼠中具有dss诱导结肠炎保护作用的Th17细胞因子IL-17A和IL-22的水平降低。综上所述，我们的研究结果表明，Dok-1和Dok-2明显通过诱导IL-17A和IL-22的表达负性调节肠道炎症。
Appropriate immune responses and mucosal barrier functions are required for the maintenance of intestinal homeostasis. Defects in this defense system may lead to inflammatory disorders such as inflammatory bowel disease. Downstream of tyrosine kinases 1 (Dok-1) and its closest homolog, Dok-2, are preferentially expressed in immune cells, and play essential roles in the negative regulation of multiple signaling pathways in both innate and adaptive immunity. However, the function of these proteins in intestinal homeostasis remained unclear. Here we show that Dok-1/-2 double knockout (DKO) mice were highly susceptible to dextran sodium sulfate (DSS)-induced colitis compared with Dok-1 or Dok-2 single KO and wild type (WT) mice. Furthermore, DSS-treated Dok-1/-2 DKO mice exhibited increased colonic tissue damage accompanied by reduced proliferation of the epithelial cells relative to WT controls, suggesting that Dok-1/-2 DKO mice have defects in the repair of intestinal epithelial lesions. In addition, the levels of the Th17 cytokines IL-17A and IL-22, which have protective roles in DSS-induced colitis, were reduced in DSS-treated Dok-1/-2 DKO mice compared with WT mice. Taken together, our results demonstrate that Dok-1 and Dok-2 negatively regulate intestinal inflammation, apparently through the induction of IL-17A and IL-22 expression.