Lack of gp130 expression results in more bacterial infection and higher mortality during chronic cholestasis in mice.
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.
Wuestefeld
Torsten
T
Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule Hannover, Hannover, Germany.
Klein
Christian
C
Streetz
Konrad L
KL
Beraza
Naiara
N
Schölmerich
Jürgen
J
Burgart
Lawrence J
LJ
Zender
Lars
L
Kubicka
Stefan
S
Baskin-Bey
Edwina
E
Gores
Gregory J
GJ
Manns
Michael P
MP
Trautwein
Christian
C
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
C494200:Il6st protein, mouse; D050796:STAT3 Transcription Factor; D000685:Serum Amyloid A Protein; C494087:Stat3 protein, mouse; D050822:Cytokine Receptor gp130