Endoplasmic reticulum stress increases the expression and function of toll-like receptor-2 in epithelial cells
Endoplasmic reticulum stress increases the expression and function of toll-like receptor-2 in epithelial cells
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DOI：
10.1016/j.bbrc.2010.09.132
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发表时间：
2010-11-12
影响因子：
3.1
通讯作者：
Kai, Hirofumi
中科院分区：
文献类型：
--
作者：
Shimasaki, Shogo;Koga, Tomoaki;Kai, Hirofumi
内质网（ER）应激与多种病理状况有关，包括神经退行性疾病、糖尿病、动脉粥样硬化、炎症和感染。内质网应激诱导炎症反应的能力被认为在这些疾病的发病机制中发挥着作用。然而，它在调节 Toll 样受体 (TLR)（识别入侵病原体的宿主防御受体）的基因表达和功能中的作用仍然未知。在这里，我们证明了几种充分表征的 ER 应激诱导剂（毒胡萝卜素、衣霉素和二硫苏糖醇）可增加上皮细胞中 TLR2 的表达。 ER 应激诱导剂也增强了 TLR2 的配体反应性，这意味着 ER 应激在调节 TLR2 依赖性炎症反应中发挥着重要作用。此外，衣霉素治疗小鼠和高脂饮食喂养小鼠肝脏中 TLR2 mRNA 水平显着增加，表明体内 ER 应激对 TLR2 表达的影响。过表达和敲低实验表明，激活转录因子 4 (ATF4)（一种 ER 应激诱导的转录因子）在 ER 应激期间诱导 TLR2 表达中的重要性。在使用 ATF4 通路激活剂 salubrinal 治疗期间，TLR2 的表达和功能增加证实了这一点。总而言之，我们的研究进一步深入了解了 ER 应激在增强宿主细菌反应或通过上调 TLR2 表达而加剧炎症状况方面的作用。 (C) 2010 Elsevier Inc. 保留所有权利。
Endoplasmic reticulum (ER) stress is involved in a wide range of pathological conditions including neurodegenerative disorders, diabetes mellitus, atherosclerosis, inflammation, and infection. The ability of ER stress to induce an inflammatory response is considered to play a role in the pathogenesis of these diseases. However, its role in regulating the gene expression and function of toll-like receptors (TLRs), host defense receptors that recognize invading pathogens, remains unknown. Here we showed that several well-characterized ER stress inducers (thapsigargin, tunicamycin, and dithiothreitol) increase the expression of TLR2 in epithelial cells. Ligand-responsiveness of TLR2 was also enhanced by ER stress inducers, implying a contributory role of ER stress for the regulation of TLR2-dependent inflammatory responses. Furthermore, there was significant increase of TLR2 mRNA level in the livers of tunicamycin-treated mice and high-fat diet-fed mice, suggesting an impact of ER stress in vivo on the expression of TLR2. Overexpression and knockdown experiments showed the importance of activating transcription factor 4 (ATF4), an ER stress-induced transcription factor, in the induction of TLR2 expression during ER stress. This was confirmed by the increased expression and function of TLR2 during treatment with salubrinal, an activator of ATF4 pathway. Taken together, our study provides further insights into the role of ER stress in enhancing host bacterial response or in exaggerating the inflammatory condition via up-regulating TLR2 expression. (C) 2010 Elsevier Inc. All rights reserved.