title: 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.
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule Hannover, Hannover, Germany.
authors.forename: Torsten
authors.initials: T
authors.lastname: Wuestefeld
authors.forename: Christian
authors.initials: C
authors.lastname: Klein
authors.forename: Konrad L
authors.initials: KL
authors.lastname: Streetz
authors.forename: Naiara
authors.initials: N
authors.lastname: Beraza
authors.forename: Jürgen
authors.initials: J
authors.lastname: Schölmerich
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: Burgart
authors.forename: Lars
authors.initials: L
authors.lastname: Zender
authors.forename: Stefan
authors.initials: S
authors.lastname: Kubicka
authors.forename: Edwina
authors.initials: E
authors.lastname: Baskin-Bey
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Gores
authors.forename: Michael P
authors.initials: MP
authors.lastname: Manns
authors.forename: Christian
authors.initials: C
authors.lastname: Trautwein
mesh_terms: D000210:Acute-Phase Reaction; D000818:Animals; D001424:Bacterial Infections / Q000453:epidemiology*; D001652:Bile Ducts / Q000601:surgery; D002779:Cholestasis / Q000378:metabolism* / Q000401:mortality* / Q000473:pathology; D002908:Chronic Disease; D050822:Cytokine Receptor gp130 / Q000172:deficiency*; D015994:Incidence; D008026:Ligation; D051379:Mice; D018345:Mice, Knockout; D050796:STAT3 Transcription Factor / Q000378:metabolism; D000685:Serum Amyloid A Protein / Q000378:metabolism
chemical_list: C494200:Il6st protein, mouse; D050796:STAT3 Transcription Factor; D000685:Serum Amyloid A Protein; C494087:Stat3 protein, mouse; D050822:Cytokine Receptor gp130