title: Contribution of TIR domain-containing adapter inducing IFN-beta-mediated IL-18 release to LPS-induced liver injury in mice.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Surgery, Hyogo College of Medicine, Nishinomiya, Japan.
authors.forename: Michiko
authors.initials: M
authors.lastname: Imamura
authors.forename: Hiroko
authors.initials: H
authors.lastname: Tsutsui
authors.forename: Koubun
authors.initials: K
authors.lastname: Yasuda
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Uchiyama
authors.forename: Shizue
authors.initials: S
authors.lastname: Yumikura-Futatsugi
authors.forename: Keiko
authors.initials: K
authors.lastname: Mitani
authors.forename: Shuhei
authors.initials: S
authors.lastname: Hayashi
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Shun-Ichiro
authors.initials: S
authors.lastname: Taniguchi
authors.forename: Nico
authors.initials: N
authors.lastname: Van Rooijen
authors.forename: Jurg
authors.initials: J
authors.lastname: Tschopp
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Jiro
authors.initials: J
authors.lastname: Fujimoto
authors.forename: Kenji
authors.initials: K
authors.lastname: Nakanishi
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology; D020170:Caspase 1 / Q000378:metabolism; D005260:Female; D006099:Granuloma / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D016899:Interferon-beta / Q000096:biosynthesis*; D020382:Interleukin-18 / Q000096:biosynthesis* / Q000097:blood; D008070:Lipopolysaccharides / Q000633:toxicity; D008099:Liver / Q000187:drug effects / Q000293:injuries* / Q000503:physiopathology; D008107:Liver Diseases / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D008264:Macrophages / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D011425:Propionibacterium acnes / Q000472:pathogenicity; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000378:metabolism
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D000255:Adenosine Triphosphate; D002352:Carrier Proteins; D020170:Caspase 1; D016899:Interferon-beta; D020382:Interleukin-18; D008070:Lipopolysaccharides; D053594:Myeloid Differentiation Factor 88; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D051197:Toll-Like Receptor 4; C507780:Myd88 protein, mouse; C492716:Nlrp3 protein, mouse; C476286:Ticam1 protein, mouse; C493487:Tlr4 protein, mouse