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首页> 外文期刊>American Journal of Physiology >Flagellin-induced tolerance of the Toll-like receptor 5 signaling pathway in polarized intestinal epithelial cells.
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Flagellin-induced tolerance of the Toll-like receptor 5 signaling pathway in polarized intestinal epithelial cells.

机译：鞭毛蛋白诱导的极化肠道上皮细胞中Toll样受体5信号通路的耐受性。

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摘要

Salmonella typhimurium is a gram-negative enteric pathogen that invades the mucosal epithelium and is associated with diarrheal illness in humans. Flagellin from S. typhimurium and other gram-negative bacteria has been shown to be the predominant proinflammatory mediator through activation of the basolateral Toll-like receptor 5 (TLR5). Recent evidence has shown that prior exposure can render immune cells tolerant to subsequent challenges by TLR ligands. Accordingly, we examined whether prior exposure to purified flagellin would render human intestinal epithelial cells insensitive to future contact. We found that flagellin-induced tolerance is common to polarized epithelial cells and prevents further activation of proinflammatory signaling cascades by both purified flagellin and Salmonella bacteria but does not affect TNF-alpha stimulation of the same pathways. Flagellin tolerance is a rapid process that does not require protein synthesis, and that occurs within 1 to 2 h of flagellin exposure. Prolonged flagellin exposure blocks activation of the NF-kappaB, MAPK, and phosphoinositol 3-kinase signaling pathways and results in the internalization of a fraction of the basolateral TLR5 without affecting the polarity or total expression of TLR5. After removal of flagellin, cells require more than 24 h to fully recover their ability to mount a normal proinflammatory response. We have found that activation of phosphoinositol 3-kinase and Akt by flagellin has a small damping effect in the early stages of flagellin signaling but is not responsible for tolerance. Our study indicates that inhibition of TLR5-associated IL-1 receptor-associated kinase-4 activity occurs during the development of flagellin tolerance and is likely to be the cause of tolerance.
机译：鼠伤寒沙门氏菌是革兰氏阴性肠病原体，会侵袭粘膜上皮，并与人类的腹泻病有关。来自鼠伤寒沙门氏菌和其他革兰氏阴性细菌的鞭毛蛋白已被证明是通过激活基底外侧Toll样受体5（TLR5）的主要促炎介质。最近的证据表明，事先暴露可使免疫细胞耐受TLR配体的后续攻击。因此，我们检查了事先接触纯化的鞭毛蛋白是否会使人肠上皮细胞对未来的接触不敏感。我们发现，鞭毛蛋白诱导的耐受性是极化上皮细胞所共有的，可防止纯化的鞭毛蛋白和沙门氏菌进一步激活促炎性信号传导级联反应，但不会影响相同途径的TNF-α刺激。鞭毛蛋白耐受性是不需要蛋白质合成的快速过程，发生在鞭毛蛋白暴露后1至2小时内。延长的鞭毛蛋白暴露会阻断NF-κB，MAPK和磷酸肌醇3激酶信号通路的激活，并导致一部分基底外侧TLR5内在化，而不会影响TLR5的极性或总表达。去除鞭毛蛋白后，细胞需要24小时以上的时间才能完全恢复正常发炎反应的能力。我们发现鞭毛蛋白激活磷酸肌醇3-激酶和Akt在鞭毛蛋白信号传导的早期阶段具有较小的阻尼作用，但对耐受性不负责。我们的研究表明，鞭毛蛋白耐受性的发展过程中发生了与TLR5相关的IL-1受体相关的激酶4活性的抑制作用，并且很可能是引起耐受的原因。

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