Contribution of TIR domain-containing adapter inducing IFN-β-mediated IL-18 release to LPS-induced liver injury in mice
Contribution of TIR domain-containing adapter inducing IFN-β-mediated IL-18 release to LPS-induced liver injury in mice
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DOI：
10.1016/j.jhep.2009.03.027
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发表时间：
2009-08-01
影响因子：
25.7
通讯作者：
Nakanishi, Kenji
中科院分区：
文献类型：
--
作者：
Imamura, Michiko;Tsutsui, Hiroko;Nakanishi, Kenji
背景/目的：用热灭活痤疮丙酸杆菌处理后，小鼠显示致密的肝肉芽肿形成。这些小鼠在用亚致死剂量LPS攻击后以白细胞介素（IL）-18依赖性方式发生肝损伤。如前所示，LPS刺激的库普弗细胞分泌IL-18，这取决于半胱天冬酶-1和Toll样受体（TLR）-4，但不依赖于其信号衔接子髓样分化因子88（MyD 88），表明另一种信号衔接子TIR结构域诱导IFN-β（TRIF）的重要性。据报道，Nalp 3炎性体控制半胱天冬酶-1活化。方法：采用ELISA法检测小鼠血清IL-18水平，ELISA法检测小鼠肝组织ALT/AST比值，ELISA法检测小鼠血清IL-18水平。结果：巨噬细胞消融小鼠无痤疮丙酸杆菌诱导的肝肉芽肿形成，无LPS诱导的血清IL-18升高和肝损伤。Myd 88（-/-）Kupffer细胞，而不是Trif（-/-）细胞，在体外TLR 4结合后表现出正常的caspase-1活化。Myd 88（-/-）小鼠在痤疮丙酸杆菌处理后没有发生肝肉芽肿，并且LPS攻击诱导了肝损伤。相反，Trif（-/-）小鼠正常形成肝肉芽肿，但不能释放IL-18或发生肝损伤。结论：痤疮丙酸杆菌处理MyD 88依赖性诱导小鼠肝肉芽肿形成。随后LPS TRIF依赖性地通过Nalp 3炎性体激活caspase-1并诱导IL-18释放，最终导致肝损伤。(C)2009年欧洲肝脏研究协会。Elsevier B. V.出版，保留所有权利。
Background/Aims: After treatment with heat-killed Propionibacterium acnes mice show dense hepatic granuloma formation. Such mice develop liver injury in an interleukin (IL)-18-dependent manner after challenge with a sublethal dose LPS. As previously shown, LPS-stimulated Kupffer cells secrete IL-18 depending on caspase-1 and Toll-like receptor (TLR)-4 but independently of its signal adaptor myeloid differentiation factor 88 (MyD88), suggesting importance of another signal adaptor TIR domain-containing adapter inducing IFN-beta (TRIF). Nalp3 inflammasome reportedly controls caspase-1 activation. Here we investigated the roles of MyD88 and TRIF in P. acnes-induced hepatic granuloma formation and LPS-induced caspase-1 activation for IL-18 release.Methods:Mice were sequentially treated with P. acnes and LPS, and their serum IL-18 levels and liver injuries were determined by ELISA and ALT/AST measurement, respectively. Active caspase-1 in LPS-stimulated Kupffer cells was determined by Western blotting.Results: Macrophage-ablated mice lacked P. acnes-induced hepatic granuloma formation and LPS-induced serum IL-18 elevation and liver injury. Myd88(-/-) Kupffer cells, but not Trif(-/-) cells, exhibited normal caspase-1 activation upon TLR4 engagement in vitro. Myd88(-/-) mice failed to develop hepatic granulomas after P. acnes treatment and liver injury induced by LPS challenge. In contrast, Trif(-/-) mice normally formed the hepatic granulomas, but could not release IL-18 or develop the liver injury. Nalp3(-/-) mice showed the same phenotypes of Trif(-/-) mice.Conclusions: Propionibacterium acnes treatment MyD88-dependently induced hepatic granuloma formation. Subsequent LPS TRIF-dependently activated caspase-1 via Nalp3 inflammasome and induced IL-18 release, eventually leading to the liver injury. (C) 2009 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.