title: Lack of hepatic c-Met and gp130 expression is associated with an impaired antibacterial response and higher lethality after bile duct ligation.
abstract: The prognosis of liver failure is often determined by infectious and cholestatic complications. As HGF/c-Met and interleukin (IL)-6/gp130 control hepatic cytoprotective pathways, we here investigated their cooperative role during the onset of cholestatic liver injury. Conditional hepatocyte-specific ((Δhepa)) c-Met, gp130 and c-Met/gp130 knockout mice (Cre-loxP system) were subjected to bile duct ligation (BDL) and lipopolysaccharide (LPS) stimulation. gp130(Δhepa) and c-Met/gp130(Δhepa) mice displayed increased lethality associated with severe bacteraemia early after BDL, whereas c-Met(Δhepa) and wild-type mice showed normal survival. Analysis of the innate immune response and the regulation of hepatic antibacterial pathways showed that the LPS-triggered hepatocellular response via the Toll-like receptor-4 pathway was regulated differentially by HGF/c-Met and IL-6/gp130. Activation of p38MAPK, c-Jun N-terminal kinase and signalling transducer and activator of transcription-3 was impaired in gp130(Δ) and c-Met(Δhepa) livers. In addition, the acute-phase response (APR) was reduced in c-Met(Δhepa) livers, whereas gp130(Δhepa) displayed a completely abolished APR. In contrast, TNF-α-dependent NF-κB activation was enhanced in gp130(Δhepa) and c-Met(Δhepa) mice and it was associated with a higher rate of apoptosis and inflammation. Moreover, expression of the neutrophil produced and secreted cathelin-related antimicrobial peptide and of genes related to the inflammasome complex correlated with the strength of the bacterial infection and with TNF-α expression. In conclusion, Gp130 and c-Met are involved in the hepatic antibacterial and innate immune response, control the APR and thus prevent sepsis and liver injury during cholestatic conditions.
authors.affiliation: Department of Medicine III, University Hospital, Aachen, Germany.
authors.forename: Arne
authors.initials: A
authors.lastname: Giebeler
authors.forename: Lars-Ove
authors.initials: LO
authors.lastname: Brandenburg
authors.forename: Michaela
authors.initials: M
authors.lastname: Kaldenbach
authors.forename: Stephanie
authors.initials: S
authors.lastname: Erschfeld
authors.forename: Hermann
authors.initials: H
authors.lastname: Wasmuth
authors.forename: Christoph
authors.initials: C
authors.lastname: Wruck
authors.forename: Christian
authors.initials: C
authors.lastname: Trautwein
authors.forename: Konrad L
authors.initials: KL
authors.lastname: Streetz
mesh_terms: D000210:Acute-Phase Reaction / Q000378:metabolism; D000818:Animals; D023181:Antimicrobial Cationic Peptides; D017209:Apoptosis / Q000502:physiology; D016470:Bacteremia / Q000378:metabolism* / Q000382:microbiology; D058491:Bacterial Load; D001652:Bile Ducts / Q000378:metabolism* / Q000382:microbiology / Q000601:surgery*; D054804:Cathelicidins / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation; D002779:Cholestasis / Q000378:metabolism; D050822:Cytokine Receptor gp130 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D007113:Immunity, Innate / Q000502:physiology; D053208:Kaplan-Meier Estimate; D019394:Ki-67 Antigen / Q000235:genetics / Q000378:metabolism; D008026:Ligation; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000293:injuries / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism
chemical_list: D023181:Antimicrobial Cationic Peptides; D054804:Cathelicidins; C494200:Il6st protein, mouse; D019394:Ki-67 Antigen; D008070:Lipopolysaccharides; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D050822:Cytokine Receptor gp130; D019859:Proto-Oncogene Proteins c-met