Activation of toll-like receptor 3 attenuates alcoholic liver injury by stimulating Kupffer cells and stellate cells to produce interleukin-10 in mice
Activation of toll-like receptor 3 attenuates alcoholic liver injury by stimulating Kupffer cells and stellate cells to produce interleukin-10 in mice
复制标题
DOI：
10.1016/j.jhep.2012.09.016
复制
发表时间：
2013-02-01
影响因子：
25.7
通讯作者：
Jeong, Won-Il
中科院分区：
文献类型：
--
作者：
Byun, Jin-Seok;Suh, Yang-Gun;Jeong, Won-Il
背景和目标：Toll样受体（TLR）4在Kupffer细胞和肝星状细胞（HSC）中的重要功能在酒精性肝损伤中已被充分证实。然而，人们对TLR 3的作用知之甚少。因此，我们测试了是否TLR 3激活的HSC和Kupffer细胞可以减轻酒精性肝损伤在体内，并探讨其可能的机制在vitro.Methods：酒精性肝损伤通过喂养野生型（WT），TLR 3基因敲除（TLR 3（-/-））和白细胞介素（IL）-10（-/-）小鼠高脂饮食加酗酒2周。为了激活TLR 3，将聚肌胞苷酸（poly I：C）注射到小鼠中。在体外研究中，HSC和枯否细胞进行了分离和治疗与聚I：C。结果：在WT小鼠，聚I：C治疗减少酒精性肝损伤和脂肪蓄积抑制核因子-κ B激活和固醇反应元件结合蛋白1C在肝脏中的表达。此外，与对照组相比，来自聚I：C处理的小鼠的新鲜分离的HSC和枯否细胞显示IL-10的表达增强。经poly I：C处理后，浸润的巨噬细胞数量和这些细胞上的肿瘤坏死因子-a、单核细胞趋化蛋白-1和IL-6的表达减少。在体外，poly I：C处理通过TLR 3依赖性机制增强HSC和Kupffer细胞中IL-10的表达。结论：TLR 3活化通过刺激HSC和Kupffer细胞产生IL-10，减轻酒精性肝损伤。TLR 3可能成为治疗酒精性肝损伤的新靶点。(C)2012年欧洲肝脏研究协会。Elsevier B. V.出版，保留所有权利。
Background & Aims: The important function of toll-like receptor (TLR) 4 in Kupffer cells and hepatic stellate cells (HSCs) has been well documented in alcoholic liver injury. However, little is known about the role of TLR3. Thus, we tested whether TLR3 activation in HSCs and Kupffer cells could attenuate alcoholic liver injury in vivo, and investigated its possible mechanism in vitro.Methods: Alcoholic liver injury was achieved by feeding wild type (WT), TLR3 knockout (TLR3(-/-)) and interleukin (IL)-10(-/-) mice with high-fat diet plus binge ethanol drinking for 2 weeks. To activate TLR3, polyinosinic-polycytidylic acid (poly I:C) was injected into mice. For in vitro studies, HSCs and Kupffer cells were isolated and treated with poly I:C.Results: In WT mice, poly I:C treatment reduced alcoholic liver injury and fat accumulation by suppressing nuclear factor-kappa B activation and sterol response element-binding protein 1c expression in the liver. In addition, freshly isolated HSCs and Kupffer cells from poly I:C-treated mice showed enhanced expression of IL-10 compared to controls. Infiltrated macrophage numbers and the expression of tumor necrosis factor-a, monocyte chemoattractant protein-1 and IL-6 on these cells were decreased after poly I:C treatment. In vitro, poly I:C treatment enhanced the expression of IL-10 via a TLR3-dependent mechanism in HSCs and Kupffer cells. Finally, the protective effects of poly I:C on alcoholic liver injury were diminished in TLR3(-/-) and IL-10(-/-) mice.Conclusions: TLR3 activation ameliorates alcoholic liver injury via the stimulation of IL-10 production in HSCs and Kupffer cells. TLR3 could be a novel therapeutic target for the treatment of alcoholic liver injury. (C) 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.