Clcn5 knockout mice exhibit novel immunomodulatory effects and are more susceptible to dextran sulfate sodium-induced colitis.
Clcn5 knockout mice exhibit novel immunomodulatory effects and are more susceptible to dextran sulfate sodium-induced colitis.
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DOI：
10.4049/jimmunol.0901657
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发表时间：
2010-04-01
期刊：
影响因子：
--
通讯作者：
Li X
中科院分区：
文献类型：
--
作者：
Alex P;Ye M;Zachos NC;Sipes J;Nguyen T;Suhodrev M;Gonzales L;Arora Z;Zhang T;Centola M;Guggino SE;Li X
虽然细胞内Cl−/H+交换器Clc-5在顶端肠内吞隔室中表达，但其在胃肠道中的病理生理作用尚不清楚。鉴于最近的发现，CLC-5是下调活动性溃疡性结肠炎（UC），我们测试的假设，损失的CLC-5调节免疫反应，从而诱导UC的易感性。在Clcn 5敲除（KO）和野生型（WT）小鼠中诱导急性葡聚糖硫酸钠（DSS）结肠炎。结肠炎，监测疾病活动指数，组织学活动指数，髓过氧化物酶活性显着升高DSS诱导的Clcn 5基因敲除小鼠与WT小鼠相比。与WT DSS结肠炎小鼠相比，DSS诱导的Clcn 5 KO小鼠的综合血清多重细胞因子谱显示Th 1-Th 17谱升高（TNF-α、IL-6和IL-17升高）。有趣的是，维持高维生素D饮食的Clcn 5 KO小鼠减弱了DSS诱导的结肠炎。结肠粘膜的免疫荧光和Western印迹分析验证了全身细胞因子模式，并进一步揭示了与WT小鼠相比，DSS诱导的Clcn 5 KO小鼠中NF-κB通路的活化增强。有趣的是，在Clcn 5 KO小鼠中观察到高基线水平的IL-6和磷酸化-I κB，表明Clc-5缺失导致的功能缺陷具有新的免疫病理作用。我们的研究表明，CLC-5的缺失1）表现出IL-6介导的免疫发病机制，2）显著加重DSS诱导的结肠炎，这受饮食因素（包括维生素D）的影响，3）描绘了明显的NF-κ B调节的Th 1-Th 17免疫失调，这意味着CLC-5在UC的免疫发病机制中的作用。
Although the intracellular Cl−/H+ exchanger Clc-5 is expressed in apical intestinal endocytic compartments, its pathophysiological role in the gastrointestinal tract is unknown. In light of recent findings that CLC-5 is downregulated in active ulcerative colitis (UC), we tested the hypothesis that loss of CLC-5 modulates the immune response, thereby inducing susceptibility to UC. Acute dextran sulfate sodium (DSS) colitis was induced in Clcn5 knockout (KO) and wild-type (WT) mice. Colitis, monitored by disease activity index, histological activity index, and myeloperoxidase activity were significantly elevated in DSS-induced Clcn5 KO mice compared with those in WT mice. Comprehensive serum multiplex cytokine profiling demonstrated a heightened Th1–Th17 profile (increased TNF-α, IL-6, and IL-17) in DSS-induced Clcn5 KO mice compared with that in WT DSS colitis mice. Interestingly, Clcn5 KO mice maintained on a high vitamin D diet attenuated DSS-induced colitis. Immunofluorescence and Western blot analyses of colonic mucosa validated the systemic cytokine patterns and further revealed enhanced activation of the NF-κB pathway in DSS-induced Clcn5 KO mice compared with those in WT mice. Intriguingly, high baseline levels of IL-6 and phospho-IκB were observed in Clcn5 KO mice, suggesting a novel immunopathogenic role for the functional defects that result from the loss of Clc-5. Our studies demonstrate that the loss of Clc-5 1) exhibits IL-6–mediated immunopathogenesis, 2) significantly exacerbated DSS-induced colitis, which is influenced by dietary factors, including vitamin D, and 3) portrays distinct NF-κB–modulated Th1–Th17 immune dysregulation, implying a role for CLC-5 in the immunopathogenesis of UC.
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DOI：
10.1152/ajplung.00121.2007
发表时间：
2007-11-01
影响因子：
4.9
作者：
Cheng, Gang;Shao, Zhifei;Agrawal, Devendra K.
通讯作者：
Agrawal, Devendra K.
影响因子：
4.5
作者：
Boonla, Chanchai;Hunapathed, Chanutra;Tosukhowong, Piyaratana
通讯作者：
Tosukhowong, Piyaratana
肥大细胞对小鼠结肠炎模型中的炎症并不重要
影响因子：
3.1
作者：
CHIN, KW;BARRETT, KE
通讯作者：
BARRETT, KE
影响因子：
5.5
作者：
Amin, Md. Ruhul;Malakooti, Jaleh;Ramaswamy, Krishnamurthy
通讯作者：
Ramaswamy, Krishnamurthy
影响因子：
2.9
作者：
BARRETT, KE;DHARMSATHAPHORN, K
通讯作者：
DHARMSATHAPHORN, K