Deletion of gp130 in myeloid cells modulates IL-6-release and is associated with more severe liver injury of Con A hepatitis.
IL-6/gp130 dependent signaling plays an important role in modulating inflammation in acute and chronic diseases. The course of Concanavalin A- (Con A) induced hepatitis can be modulated by different immune-mediated mechanisms. IL-6/gp130-dependent signaling has been shown to be protective in hepatocytes. However, the role of this pathway in myeloid cells has not yet been studied. In our present study we used macrophage/neutrophil-specific gp130 knockout (gp130(ΔLys), KO) animals and analyzed its relevance in modulating Con A-induced hepatitis. Additionally, we performed in vitro studies with gp130(ΔLys)-macrophages. We demonstrate that gp130(ΔLys) animals are more susceptible to Con A-induced hepatitis. This is reflected by higher transaminases, higher lethality and more severe liver injury as shown by histological staining. Using flow cytometry analysis we further could show that increased liver injury of gp130(ΔLys) animals is associated with a stronger infiltration of CD11b/F4/80 double-positive cells compared to wild-type (gp130(flox/flox), WT) controls. To further characterize our observations we studied thioglycolate-elicited peritoneal macrophages from gp130(ΔLys) animals. Interestingly, the LPS-dependent IL-6 release in gp130(ΔLys) macrophages is significantly reduced (p<0.05) compared to WT macrophages. Additionally, IL-6 blood levels in vivo after Con A injection were significantly lower in gp130(ΔLys) animals compared to WT animals (p<0.05). In summary, our results suggest that gp130-deletion in macrophages and granulocytes leads to diminished IL-6 release from these cells, which is associated with more severe Con A-induced hepatitis.
Department of Gastroenterology and Metabolic Disorders, RWTH University Hospital Aachen, University of Aachen (RWTH), Pauwelsstrasse 30, 52074 Aachen, Germany.
H H
HH
Lutz
S D
SD
Sackett
D C
DC
Kroy
N
N
Gassler
C
C
Trautwein
D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics / Q000276:immunology*; D003208:Concanavalin A; D050822:Cytokine Receptor gp130 / Q000172:deficiency* / Q000235:genetics / Q000276:immunology; D004195:Disease Models, Animal; D007150:Immunohistochemistry; D015850:Interleukin-6 / Q000276:immunology*; D008099:Liver / Q000187:drug effects / Q000276:immunology / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000276:immunology* / Q000378:metabolism
C494200:Il6st protein, mouse; D015850:Interleukin-6; D003208:Concanavalin A; D050822:Cytokine Receptor gp130