Lack of hepatic c-Met and gp130 expression is associated with an impaired antibacterial response and higher lethality after bile duct ligation

作者：Giebeler Arne; Brandenburg Lars Ove; Kaldenbach Michaela; Erschfeld Stephanie; Wasmuth Hermann; Wruck Christoph; Trautwein Christian; Streetz Konrad L^*

来源：Laboratory Investigation, 2012, 92(12): 1726-1737.

DOI：10.1038/labinvest.2012.122

• acute-phase response
• bile duct ligation
• C-Met
• gp130
• innate immune response

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 ((Delta hepa)) c-Met, gp130 and c-Met/gp130 knockout mice (Cre-loxP system) were subjected to bile duct ligation (BDL) and lipopolysaccharide (LPS) stimulation. gp130(Delta hePa) and c-Met/gp130(Delta hepa) mice displayed increased lethality associated with severe bacteraemia early after BDL, whereas c-met(Delta hepa) 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(Delta) and c-Met(Delta hepa) livers. In addition, the acute-phase response (APR) was reduced in c-Met(Delta hepa) livers, whereas gp130(Delta hepa) displayed a completely abolished APR. In contrast, TNF-alpha-dependent NE-kappa B activation was enhanced in gp130(Delta hepa) and c-Met(Delta hepa) 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 inflannmasome complex correlated with the strength of the bacterial infection and with TNF-alpha 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. Laboratory Investigation (2012) 92, 1726-1737; doi:10.1038/labinvest.2012.122; published online 17 September 2012

• 出版日期2012-12