炎症反应中Toll样受体对NHE蛋白家族的调节
车浩, 阮语嫣, 骆汤艳, 陈明敏^*
绍兴文理学院医学院，绍兴 312000
摘要
Toll样受体(Toll-like receptors, TLRs)在不同的天然免疫应答中可以识别和激活不同的病原体相关分子模式(pathogen- associated molecular patterns, PAMPs)，进而导致炎症。而钠氢交换体(Na+/H+ exchanger, NHE)不仅具有调节胞内pH值和细胞容积、维持腔体微环境、影响营养吸收的作用，而且与细胞的增殖、迁移、凋亡相关。在炎症情况下，NHE的活性和膜蛋白表达都受到抑制。结肠上皮细胞TLR2激活后可通过MyD88非依赖性途径抑制NHE1活性，其抑制作用的机制与Src的聚集和PI3Ks的磷酸化有关。长期脂多糖(lipopolysaccharides, LPS)暴露可激活肠巨噬细胞TLR4，通过MyD88依赖性途径(即TLR4/MyD88/NF-κB通路)导致炎症发生，并加速NHE1胞内降解，从而抑制NHE1活性；但短时间LPS暴露却提高NHE1活性。TLR5的激活可使NHE3活性增高。结肠炎患者和模型动物肠道巨噬细胞NHE3活性或/和表达量下降。在肾小管上皮细胞中，基底侧LPS刺激通过激活TLR4/MyD88/MAPK/ERK信号通路抑制管腔侧NHE3的活性，而管腔侧LPS刺激则激活TLR4/MyD88依赖性PI3K-AKT-mTOR信号通路，引起基底侧NHE1活性抑制，进而继发影响管腔侧NHE3功能。


关键词： Toll样受体; 钠氢交换体; 感染; 炎症性肠病
分类号：R363.2;R333.3;R334.1

The regulation of Na+/H+ exchangers by Toll-like receptors under inflammation
CHE Hao, RUAN Yu-Yan, LUO Tang-Yan, CHEN Ming-Min^*
Medical School, Shaoxing University, Shaoxing 312000, China
Abstract
Toll-like receptors (TLRs) can be recognized and activated by different pathogen associated molecular patterns (PAMPs), which induce innate immune response and inflammation of the body. Na+/H+ exchangers (NHEs) not only play roles in the regulation of cellular pH and cell volume, maintenance of the cavity microenvironment and nutrients absorption, but also are related to cell proliferation, migration and apoptosis. The activity and membrane protein expression of NHEs are inhibited under the inflammation condition. It has been shown that the activation of TLR2 in colon epithelial cells can inhibit the activity of NHE1 through MyD88 independent pathway, which involves the recruitment of Src and the phosphorylation of PI3Ks. Other studies on intestinal macrophage showed long-term LPS stimulation can induce TLR4 activation through MyD88-dependent pathway (TLR4/MyD88/NF-κB) and induce inflammation and degeneration of intracellular NHE1, which leads to NHE1 activity inhibition. But short-term LPS exposure increases the activity and protein expression of NHE1. The activation of TLR5 increases the activity of NHE3. The activity and/or expression of NHE3 in intestinal macrophages in colitis patients and model animals were decreased. In renal tubular epithelial cells, basolateral LPS stimulation inhibits luminal NHE3 activation through TLR4/MyD88-dependent MAPK/ERK signaling pathway. And LPS stimulation on the lumen side activates TLR4/MyD88-dependent PI3K-AKT-mTOR signaling pathway, which results in the inhibition of NHE1 activity in basolateral side, and then affects the NHE3 function of the lumen side.


Key words: Toll-like receptors; Na+/H+ exchanger; infection; inflammatory bowel disease

收稿日期：2018-05-24　　录用日期：2018-10-24
通讯作者：陈明敏　　E-mail: ellechen80@hotmail.com
DOI: 10.13294/j.aps.2018.0069
引用本文：
车浩, 阮语嫣, 骆汤艳, 陈明敏. 炎症反应中Toll样受体对NHE蛋白家族的调节[J]. 生理学报 2018; 70 (5): 521-530.
CHE Hao, RUAN Yu-Yan, LUO Tang-Yan, CHEN Ming-Min. The regulation of Na+/H+ exchangers by Toll-like receptors under inflammation. Acta Physiol Sin 2018; 70 (5): 521-530 (in Chinese with English abstract).



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