TNFα-induced and berberine-antagonized tight junction barrier impairment via tyrosine kinase, Akt and NFκB signaling
TNFα-induced and berberine-antagonized tight junction barrier impairment via tyrosine kinase, Akt and NFκB signaling
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DOI：
10.1242/jcs.070896
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发表时间：
2010-12-01
影响因子：
4
通讯作者：
Schulzke, Joerg-Dieter
中科院分区：
文献类型：
--
作者：
Amasheh, Maren;Fromm, Anja;Schulzke, Joerg-Dieter
TNF α介导的紧密连接缺陷导致炎症性肠病（IBD）腹泻。在我们的研究中，在HT-29/B6人结肠单层中分析了TNF α对屏障或孔形成claudins作用的信号通路。小檗碱是一种草药治疗剂，最近被确定为糖尿病和高胆固醇血症的治疗药物，能够完全拮抗细胞模型和大鼠结肠中TNF α介导的屏障缺陷。Ussing室实验和双通道阻抗谱显示，TNF α后细胞旁电阻降低至11 +/-4%，而跨细胞电阻不变。细胞旁标记荧光素的渗透性增加了四倍。单独的黄连素没有效果，但它完全防止了TNF α诱导的屏障缺陷。在大鼠结肠中证实了这种对耐药性的影响。TNF α从紧密连接中去除了claudin-1，并增加了claudin-2的表达。小檗碱阻止TNF α诱导的claudin-1分解和claudin-2的上调。染料木黄酮加BAY 11 -7082可模拟小檗碱的作用，表明它们通过酪氨酸激酶、pAkt和NF κ B途径介导。总之，小檗碱的抗溃疡作用是由一种新的机制解释的，这表明了一种治疗肠道炎症屏障破坏的方法。
TNF alpha-mediated tight junction defects contribute to diarrhea in inflammatory bowel diseases (IBDs). In our study, the signaling pathways of the TNF alpha effect on barrier- or pore-forming claudins were analyzed in HT-29/B6 human colon monolayers. Berberine, a herbal therapeutic agent that has been recently established as a therapy for diabetes and hypercholesterinemia, was able to completely antagonize the TNF alpha-mediated barrier defects in the cell model and in rat colon. Ussing chamber experiments and two-path impedance spectroscopy revealed a decrease of paracellular resistance after TNF alpha to 11 +/- 4%, whereas transcellular resistance was unchanged. The permeability of the paracellular marker fluorescein was increased fourfold. Berberine alone had no effect while it fully prevented the TNF alpha-induced barrier defects. This effect on resistance was confirmed in rat colon. TNF alpha removed claudin-1 from the tight junction and increased claudin-2 expression. Berberine prevented TNF alpha-induced claudin-1 disassembly and upregulation of claudin-2. The effects of berberine were mimicked by genistein plus BAY11-7082, indicating that they are mediated via tyrosine kinase, pAkt and NF kappa B pathways. In conclusion, the anti-diarrheal effect of berberine is explained by a novel mechanism, suggesting a therapeutic approach against barrier breakdown in intestinal inflammation.