Crosstalk between NF-κB and β-catenin pathways in bacterial-colonized intestinal epithelial cells
Crosstalk between NF-κB and β-catenin pathways in bacterial-colonized intestinal epithelial cells
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DOI：
10.1152/ajpgi.00515.2004
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发表时间：
2005-07-01
影响因子：
4.5
通讯作者：
Madara, JL
中科院分区：
文献类型：
--
作者：
Sun, J;Hobert, ME;Madara, JL
已知沙门氏菌与上皮细胞的相互作用会激活促炎性 NF-κ B 信号通路，最近发现它还会影响 β-连环蛋白信号通路，而β-连环蛋白信号通路是上皮细胞增殖和分化的重要调节因子。在这里，使用极化上皮细胞模型，我们证明这些相同的细菌介导的效应也指导 NF-κ B 和 β-catenin 信号通路之间的分子串扰。这两条途径的汇聚是 NF-kappa B p50 亚基和 β-连环蛋白之间直接相互作用的结果。我们发现，野生型沙门氏菌菌株的无毒衍生物 PhoP(c) 通过稳定 β-连环蛋白与 NF-kappa B 的结合来减弱 NF-kappa B 活性。在表达组成型活性 β-连环蛋白的细胞系中，I kappa B α 蛋白间接稳定，并且在野生型沙门氏菌定植后 NF-kappa B 活性受到抑制。因此，发现组成型活性β-连环蛋白抑制IL-8的分泌。因此，我们的研究结果强烈表明，β-连环蛋白和 NF-κ B 信号通路之间的串扰是肠道炎症的重要调节因子。
Salmonella-epithelial cell interactions are known to activate the proinflammatory NF-kappa B signaling pathway and have recently been found to also influence the beta-catenin signaling pathway, an important regulator of epithelial cell proliferation and differentiation. Here, using polarized epithelial cell models, we demonstrate that these same bacteria-mediated effects also direct the molecular crosstalk between the NF-kappa B and beta-catenin signaling pathways. Convergence of these two pathways is a result of the direct interaction between the NF-kappa B p50 subunit and beta-catenin. We show that PhoP(c), the avirulent derivative of a wild-type Salmonella strain, attenuates NF-kappa B activity by stabilizing the association of beta-catenin with NF-kappa B. In cell lines expressing constitutively active beta-catenin, I kappa B alpha protein was indirectly stabilized and NF-kappa B activity was repressed after wild-type Salmonella colonization. Accordingly, constitutively active beta-catenin was found to inhibit the secretion of IL-8. Thus our findings strongly suggest that the crosstalk between the beta-catenin and NF-kappa B signaling pathways is an important regulator of intestinal inflammation.