Mkp-1 cross-talks with Nrf2/Ho-1 pathway protecting against intestinal inflammation
Mkp-1 cross-talks with Nrf2/Ho-1 pathway protecting against intestinal inflammation
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Mkp-1 与 Nrf2/Ho-1 通路交叉对话可预防肠道炎症
DOI：
10.1016/j.freeradbiomed.2018.07.002
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发表时间：
2018-08-20
影响因子：
7.4
通讯作者：
Tang, Xiuwen
中科院分区：
文献类型：
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作者：
Li, Jing;Wang, Hongyan;Tang, Xiuwen
炎症性肠病(IBD)与强烈的氧化应激有关，导致结肠损伤和肿瘤发生。丝裂原活化蛋白激酶磷酸酶1(MKP-1)是天然免疫应答的重要负性调节因子。然而，它在结肠炎中的作用，以及它与核因子-红系2相关因子2(Nrf2)在炎症反应中的作用尚不清楚，Nrf2是对抗氧化应激的细胞保护计划的主要调节因子。在这项研究中，我们发现MKP-1、Nrf2和HO-1在溃疡性结肠炎和克罗恩病患者以及葡聚糖硫酸钠(DSS)诱导的野生型结肠炎小鼠的结肠组织中的表达增加是相关的。MKP-1(-/-)小鼠更易患DSS诱导的结肠炎，并伴有更严重的隐窝损伤和炎症。在机制上，MKP-1直接与Nrf2的DIDLID基序相互作用，增加了Nrf2的稳定性，并正向调节内毒素(LPS)诱导的Nrf2/HO-1的表达。相反，在暴露于内毒素时，Nrf2通过MKP-1启动子中的抗氧化反应元件激活MKP-1的转录。我们的结果揭示了MKP-1和Nrf2信号通路之间在保护结肠炎症方面的新联系。MKP-1可能是IBD的治疗靶点。
Inflammatory bowel disease (IBD) is associated with intense oxidative stress, contributes to colonic damage and tumorigenesis. Mitogen-activated protein kinase phosphatase 1 (Mkp-1) is an essential negative regulator of the innate immune response. However, its role in colitis, and its association with the nuclear factor-erythroid 2 related factor 2 (Nrf2), a master regulator of cytoprotection program against oxidative stress, in inflammatory response, is elusive. In this study, we found that increased expression of Mkp-1, Nrf2, and heme oxygenase 1 (Ho-1) was correlated in colonic tissues in patients with ulcerative colitis and Crohn's disease, as well as wild type mice with colitis induced by dextran sodium sulfate (DSS). Mkp-1(-/-) mice were more susceptible to DSS-induced colitis with more severe crypt injury and inflammation. Mechanistically, directly interacting with the DIDLID motif of Nrf2, Mkp-1 increased Nrf2 stability and positively regulated the constitutive and lipopolysaccharide (LPS)-inducible Nrf2/Ho-1 expression. Conversely, upon exposure to LPS, Nrf2 activated Mkp-1 transcription through the antioxidant response elements in the promoter of Mkp-1. Our results revealed a novel link between Mkp-1 and Nrf2 signaling pathways in protecting against colonic inflammation. Mkp-1 might be a therapeutic target for IBD.