| First Author | Giebeler A | Year | 2012 |
| Journal | Lab Invest | Volume | 92 |
| Issue | 12 | Pages | 1726-37 |
| PubMed ID | 22986785 | Mgi Jnum | J:190339 |
| Mgi Id | MGI:5448613 | Doi | 10.1038/labinvest.2012.122 |
| Citation | Giebeler A, et al. (2012) Lack of hepatic c-Met and gp130 expression is associated with an impaired antibacterial response and higher lethality after bile duct ligation. Lab Invest 92(12):1726-37 |
| abstractText | 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 ((Deltahepa)) c-Met, gp130 and c-Met/gp130 knockout mice (Cre-loxP system) were subjected to bile duct ligation (BDL) and lipopolysaccharide (LPS) stimulation. gp130(Deltahepa) and c-Met/gp130(Deltahepa) mice displayed increased lethality associated with severe bacteraemia early after BDL, whereas c-Met(Deltahepa) 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(Deltahepa) livers. In addition, the acute-phase response (APR) was reduced in c-Met(Deltahepa) livers, whereas gp130(Deltahepa) displayed a completely abolished APR. In contrast, TNF-alpha-dependent NF-kappaB activation was enhanced in gp130(Deltahepa) and c-Met(Deltahepa) 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-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. |
