Contribution of TIR domain-containing adapter inducing IFN-beta-mediated IL-18 release to LPS-induced liver injury in mice

M. Imamura, H. Tsutsui, K. Yasuda, R. Uchiyama, S. Yumikura-Futatsugi, K. Mitani, S. Hayashi, S Akira, S. Taniguchi, N. van Rooijen, J. Tschopp, T. Yamamoto, J. Fujimoto, K. Nakanishi

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Abstract

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
Original languageUndefined/Unknown
Pages (from-to)333-341
JournalJournal of Hepatology
Volume51
Issue number2
DOIs
Publication statusPublished - 2009

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Imamura, M., Tsutsui, H., Yasuda, K., Uchiyama, R., Yumikura-Futatsugi, S., Mitani, K., ... Nakanishi, K. (2009). Contribution of TIR domain-containing adapter inducing IFN-beta-mediated IL-18 release to LPS-induced liver injury in mice. Journal of Hepatology, 51(2), 333-341. https://doi.org/10.1016/j.jhep.2009.03.027