Critical Roles of Notch and Wnt/β-Catenin Pathways in the Regulation of Hyperplasia and/or Colitis in Response to Bacterial Infection
Critical Roles of Notch and Wnt/β-Catenin Pathways in the Regulation of Hyperplasia and/or Colitis in Response to Bacterial Infection
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DOI：
10.1128/iai.00236-12
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发表时间：
2012-09-01
影响因子：
3.1
通讯作者：
Umar, Shahid
中科院分区：
文献类型：
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作者：
Ahmed, Ishfaq;Chandrakesan, Parthasarathy;Umar, Shahid
Notch和Wnt/β-catenin信号在肠道发育和稳态中起重要作用。啮齿类柠檬酸杆菌根据遗传背景诱导可传播的小鼠结肠增生（TMCH）和不同程度的炎症。我们旨在阐明Notch和Wnt/β-连环蛋白通路在C.啮齿类感染在TMCH期间，Notch细胞内结构域（NICD）的相对水平显著增加，沿着Jagged-1和Hes-1的增加，与增生的进展和消退阶段一致。在增生开始前用二苯并氮杂卓（DBZ）阻断Notch信号传导5天也阻断了Wnt/β-连环蛋白信号传导。在增生开始后靶向Notch途径5天未能抑制Wnt/β-连环蛋白调节的隐窝增生。长期给予DBZ 10天阻断Notch和Wnt信号传导，破坏肠屏障，并诱导结肠炎。Core-3（-/-）小鼠，粘蛋白分泌缺陷，易受结肠炎实验触发因素的影响，在对C.啮齿类加DBZ。在这些小鼠中，长期给予DBZ不会导致隐窝中假定的干细胞标记物双皮质素样激酶-1（DCLK 1）耗竭。膳食bael（Aegle marmelos）提取物（4%）和姜黄素（4%）通过Notch和Wnt/β-catenin途径恢复信号传导，从而促进隐窝再生，并补充粘液层，从而改善C。啮齿类和DBZ诱导的NIH结肠炎：瑞士小鼠。因此，细胞增殖和粘液产生之间的平衡作用以恢复屏障完整性似乎取决于TMCH模型中Wnt/β-连环蛋白和Notch途径之间的相互作用。
Notch and Wnt/beta-catenin signals play essential roles in intestinal development and homeostasis. Citrobacter rodentium induces transmissible murine colonic hyperplasia (TMCH) and various degrees of inflammation, depending upon the genetic background. We aimed at delineating the role of the Notch and Wnt/beta-catenin pathways in the regulation of colonic crypt hyperplasia and/or colitis following C. rodentium infection. During TMCH, relative levels of the Notch intracellular domain (NICD) increased significantly, along with increases in Jagged-1 and Hes-1 coinciding with the progression and regression phases of hyperplasia. Blocking of Notch signaling with dibenzazepine (DBZ) for 5 days before the onset of hyperplasia also blocked Wnt/beta-catenin signaling. Targeting the Notch pathway for 5 days after the onset of hyperplasia failed to inhibit Wnt/beta-catenin-regulated crypt hyperplasia. Chronic DBZ administration for 10 days blocked both Notch and Wnt signaling, disrupted the intestinal barrier, and induced colitis. Core-3(-/-) mice, which are defective in mucin secretion and are susceptible to experimental triggers of colitis, also exhibited significant colitis in response to C. rodentium plus DBZ. Chronic DBZ administration in these mice did not result in depletion of the putative stem cell marker doublecortin-like kinase-1 (DCLK1) in the crypts. Dietary bael (Aegle marmelos) extract (4%) and curcumin (4%) restored signaling via the Notch and Wnt/beta-catenin pathways, thereby promoting crypt regeneration, and also replenished the mucus layer, leading to amelioration of C. rodentium- and DBZ-induced colitis in NIH: Swiss mice. Thus, the balancing act between cell proliferation and mucus production to restore barrier integrity seems to depend upon the interplay between the Wnt/beta-catenin and Notch pathways in the TMCH model.