Contribution of interleukin-6/gp 130 signaling in hepatocytes to the inflammatory response in mice infected with Streptococcus pyogenes.
BACKGROUND
Sepsis and septic shock caused by gram-positive bacteria have become increasingly frequent clinical problems. These conditions are accompanied by an overwhelming inflammation in which the liver plays a central role as a source and target of inflammatory mediators. Sepsis is still associated with high mortality rates, and new intervention strategies directed at ameliorating the extent of the inflammatory reaction are strongly needed. Here, we investigated whether blockage of the transducer gp130, a receptor involved in the regulation of the inflammatory response, might be useful in the treatment of experimental gram-positive sepsis.


METHODS
An experimental model of gram-positive sepsis was used in which liver-specific gp130-deficient mice (FVB/n alfpCre+ gp130(LoxP/LoxP)) and wild-type mice (FVB/n gp130(LoxP/LoxP)) were intravenously infected with Streptococcus pyogenes. The following parameters were monitored: mortality, bacterial loads in systemic organs, serum inflammatory cytokine levels, and organ damage.


RESULTS
We show that infected gp130-deficient mice survived significantly longer, had lower bacterial loads, and developed organ damage more slowly than infected wild-type mice. Furthermore, levels of interferon- gamma , interleukin-6, and the chemokine cytokine-induced neutrophil chemoattractant were significantly lower in gp130-deficient mice than in wild-type mice. Histopathological examination of livers showed lower amounts of neutrophil infiltration, apoptosis, and tissue damage in infected gp130-deficient mice than in wild-type mice.


CONCLUSIONS
Our results demonstrate that the gp130 receptor is involved in the regulation of inflammation during gram-positive sepsis and that blockage of gp130 signaling in hepatocytes could constitute a novel target for adjunctive therapy in patients with sepsis.
Medizinische Klinik III, University Hospital Aachen, Rheinisch-Westfalisch Techniche Hochschule Aachen, Aachen, Germany. christian.klein@dife.de
Christian
C
Klein
Eva
E
Medina
Leif
L
Sander
Uta
U
Dierssen
Tania
T
Roskams
Werner
W
Mueller
Christian
C
Trautwein
Oliver
O
Goldmann
D000818:Animals; D050822:Cytokine Receptor gp130 / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism*; D051379:Mice; D018805:Sepsis / Q000378:metabolism / Q000382:microbiology; D015398:Signal Transduction; D013290:Streptococcal Infections / Q000378:metabolism*; D013297:Streptococcus pyogenes / Q000502:physiology*
C494200:Il6st protein, mouse; D015850:Interleukin-6; D050822:Cytokine Receptor gp130