Hu Xuelian, Wang Peng, Du Junfeng, Yang Fan, Tian Yuan, Shen Xiaofei, Yang Tao, Zhang Lianfeng, Zhao Yong
*State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China; †Department of General Surgery, General Hospital of Beijing Military Command, Beijing, China; and ‡Key Laboratory of Human Diseases Comparative Medicine, Ministry of Health, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Inflamm Bowel Dis. 2016 Jun;22(6):1316-25. doi: 10.1097/MIB.0000000000000751.
Wild-type p53-induced phosphatase 1 (Wip1) is currently believed to be a promising drug target for cancer therapy. Our recent studies showed that deletion of Wip1 remarkably promoted neutrophil inflammatory response. Whether Wip1 is involved in the regulation of inflammatory bowel disease is unknown. In the present study, we found that Wip1 knockout (KO) mice were more susceptible to colitis induced by dextran sulphate sodium (DSS) than wild-type mice as substantiated by the lower mouse survival ratio, rapid bodyweight loss, increased disease activity index, shorter colon length, and more severe pathology of colons in Wip1KO mice. Using full bone marrow chimera mouse models, we demonstrated that Wip1 intrinsically controls inflammatory response of immune cells. Deletion of IL-17 (Wip1/IL-17 double KO mice) significantly rescued the pathology in Wip1KO mice. Neutrophils of DSS-treated wild-type and Wip1KO mice expressed significantly higher IL-17. After adoptive transfer of sorted Wip1KO or double KO neutrophils into IL-17KO mice, mice receiving double KO neutrophils were more resistant to DSS-induced colitis than mice receiving Wip1KO neutrophils. These data collectively indicate that Wip1 modulates host sensitivity to colitis by intrinsically regulating immune cells. The enhanced IL-17 expression in neutrophils contributed to the increased sensitivity and severity of colitis in Wip1KO mice. Thus, Wip1 may be used as a drug target to treat colitis.
野生型p53诱导的磷酸酶1（Wip1）目前被认为是癌症治疗中一个有前景的药物靶点。我们最近的研究表明，Wip1的缺失显著促进了中性粒细胞的炎症反应。Wip1是否参与炎症性肠病的调节尚不清楚。在本研究中，我们发现Wip1基因敲除（KO）小鼠比野生型小鼠更容易受到葡聚糖硫酸钠（DSS）诱导的结肠炎影响，这体现在Wip1基因敲除小鼠的存活率更低、体重快速下降、疾病活动指数增加、结肠长度缩短以及结肠病理更严重。使用全骨髓嵌合小鼠模型，我们证明Wip1内在地控制免疫细胞的炎症反应。IL-17的缺失（Wip1/IL-17双基因敲除小鼠）显著挽救了Wip1基因敲除小鼠的病理状态。经DSS处理的野生型和Wip1基因敲除小鼠的中性粒细胞表达的IL-17显著更高。将分选的Wip1基因敲除或双基因敲除的中性粒细胞过继转移到IL-17基因敲除小鼠后，接受双基因敲除中性粒细胞的小鼠比接受Wip1基因敲除中性粒细胞的小鼠对DSS诱导的结肠炎更具抵抗力。这些数据共同表明，Wip1通过内在调节免疫细胞来调节宿主对结肠炎的敏感性。Wip1基因敲除小鼠中性粒细胞中IL-17表达的增强导致了结肠炎敏感性和严重程度的增加。因此，Wip1可能用作治疗结肠炎的药物靶点。
