Lack of gp130 Expression Results in More Bacterial Infection and Higher Mortality During Chronic Cholestasis in Mice *

Abstract

Chronic cholestasis is associated with increased bacterial infections and sepsis resulting in higher mortality in humans. In the current study, we investigated the relevance of gp130-dependent pathways after bile duct ligation (BDL). BDL was performed in conditional gp130 knockout (loxP/Cre system) mice and respective controls. Liver injury, regulation of the acute phase response, and the impact on survival and bacterial infections were determined. Acute BDL resulted in increased IL-6 levels, Stat3 activation, and an increase in acute-phase proteins (serum-amyloid-A [SAA]), which was blocked in gp130-deleted animals. In addition, the antimicrobial gene hepcidin was regulated in a gp130-dependent manner after BDL. During chronic cholestasis Stat3 activation was dramatically reduced, while high SAA levels were maintained via gp130-dependent signaling. Inhibition of gp130-dependent pathways resulted in higher mortality and liver damage, which was associated with higher infiltration of immune-activated cells and increased germ number in the liver. In conclusion, during acute and chronic cholestasis, the gp130 system is essential for controlling the acute-phase response. Lack of gp130 expression results in pronounced bacterial growth in bile and liver after BDL, which is associated with higher mortality. Activation of gp130-dependent pathways after BDL is essential and appears to be a therapeutic target during cholestasis. (HEPATOLOGY 2005; 42:1082-1090.)

Bile acids inhibit interleukin-6 signaling via gp130 receptor-dependent and -independent pathways in rat liver

“…11 Moreover, mice with hepatocyte-specific gp130 gene knockout suffer from increased bacterial infections of the biliary tract and higher mortality during chronic cholestasis. These studies support the view that the IL-6/gp130/Jak/STAT cascade mediates hepatoprotective effects 9,12,13 that are counteracted by TNF-␣, ethanol, and, as suggested by our study, proapoptotic bile acids.…”

Constitutive androstane receptor (CAR) ligand, TCPOBOP, attenuates Fas-induced murine liver injury by altering Bcl-2 proteins

“…Antigen retrieval was performed as previously described. 34 Thereafter, the catalyzed signal amplification system (DAKO, Carpinteria, CA) was used for both PCNA and ␣SMA staining according to the manufacturer's instructions. The primary antibodies used were anti-PCNA (Santa Cruz Biotech, Santa Cruz, CA) and anti-␣SMA (Ab1; NeoMarkers, Fremont, CA) mouse monoclonal antibodies, both used at a dilution of 1:400.…”

Cholestasis downregulate hepcidin expression through inhibiting IL-6-induced phosphorylation of signal transducer and activator of transcription 3 signaling

“…Interestingly, chronic cholestatic mice without gp130 expression results in more bacterial infection and higher mortality, which confirmed the importance of gp130 in innate immunity and IL-6 signaling. 37 Intrahepatic STAT-3 activation predicted the outcome, 38 and STAT3 knockout mice showed significantly higher mortality than the wide type after cecal ligation and puncture sepsis. 39 Kano et al 40 have shown that STAT3 signaling within endothelia has as a critical anti-inflammatory mediator against endotoxin-induced inflammation.…”