Article: article from journal or magazin.
Contribution of TIR domain-containing adapter inducing IFN-beta-mediated IL-18 release to LPS-induced liver injury in mice.
Journal of hepatology
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.
Adaptor Proteins, Vesicular Transport/deficiency, Adaptor Proteins, Vesicular Transport/genetics, Adenosine Triphosphate/metabolism, Animals, Carrier Proteins/genetics, Carrier Proteins/physiology, Caspase 1/metabolism, Female, Granuloma/etiology, Granuloma/pathology, Interferon-beta/biosynthesis, Interleukin-18/biosynthesis, Interleukin-18/blood, Lipopolysaccharides/toxicity, Liver/drug effects, Liver/injuries, Liver Diseases/etiology, Liver Diseases/pathology, Macrophages/physiology, Mice, Mice, Inbred C57BL, Mice, Knockout, Myeloid Differentiation Factor 88/deficiency, Myeloid Differentiation Factor 88/genetics, Propionibacterium acnes/pathogenicity, Signal Transduction, Toll-Like Receptor 4/metabolism
Web of science
Last modification date