Maintenance of colonic homeostasis by distinctive apical TLR9 signalling in intestinal epithelial cells
Maintenance of colonic homeostasis by distinctive apical TLR9 signalling in intestinal epithelial cells
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DOI：
10.1038/ncb1500
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发表时间：
2006-12-01
影响因子：
21.3
通讯作者：
Raz, Eyal
中科院分区：
文献类型：
--
作者：
Lee, Jongdae;Mo, Ji-Hun;Raz, Eyal
肠道细菌抑制肠道炎症信号的机制仍不清楚。在这里，我们提出了一种细胞机制，即肠上皮细胞（IEC）的极性在结肠内稳态中起着重要作用。通过顶端和基底外侧表面结构域的TLR9活化具有不同的转录应答，这通过NF-κ B活化和cDNA微阵列分析得到证实。尽管基底外侧TLR9信号传导I κ B α降解和NF-κ B途径的活化，但顶端TLR9刺激引起独特的应答，其中泛素化的I κ Ba在细胞质中积累，阻止NF-κ B活化。此外，顶端TLR9刺激赋予细胞内耐受随后的TLR挑战。与野生型和TLR 2缺陷小鼠相比，TLR 9缺陷小鼠的IEC显示出较低的NF-κ B激活阈值，这些小鼠对实验性结肠炎高度易感。我们的数据提供了一个器官特异性先天免疫的情况下，TLR表达极化的IEC独特的进化，以维持结肠稳态和调节耐受性和炎症。
The mechanisms by which commensal bacteria suppress inflammatory signalling in the gut are still unclear. Here, we present a cellular mechanism whereby the polarity of intestinal epithelial cells (IECs) has a major role in colonic homeostasis. TLR9 activation through apical and basolateral surface domains have distinct transcriptional responses, evident by NF-kappa B activation and cDNA microarray analysis. Whereas basolateral TLR9 signals I kappa B alpha degradation and activation of the NF-kappa B pathway, apical TLR9 stimulation invokes a unique response in which ubiquitinated I kappa Ba accumulates in the cytoplasm preventing NF-kappa B activation. Furthermore, apical TLR9 stimulation confers intracellular tolerance to subsequent TLR challenges. IECs in TLR9-deficient mice, when compared with wild-type and TLR2-deficient mice, display a lower NF-kappa B activation threshold and these mice are highly susceptible to experimental colitis. Our data provide a case for organ-specific innate immunity in which TLR expression in polarized IECs has uniquely evolved to maintain colonic homeostasis and regulate tolerance and inflammation.