The regulation of liver cell survival by complement.
Complement effectors are known to contribute to host cell injury in several inflammatory diseases. Contrary to this paradigm, in this study utilizing surgical liver resection (partial hepatectomy) in various complement-deficient mice as a model, we have demonstrated that complement anaphylatoxins C3a and C5a are required for the survival of liver cells during regeneration. The mechanisms of these cytoprotective functions of complement were related to the regulation of IL-6 and TNF production or release after liver resection. Disturbances in the cytokine milieu, induced by a loss of complement activity, were found to alter prosurvival signaling, including the IL-6/STAT3 and PI3K/Akt/mammalian target of rapamycin pathways. In conclusion, this study documents functions of complement proteins as prosurvival factors that, through their interactions with cytokines, inhibit apoptotic signaling in proliferating cells of epithelial origin.
Markiewski
Maciej M
MM
Department of Pathology and Laboratory Medicine, Medical School of the University of Pennsylvania, Philadelphia, PA 19104, USA.
DeAngelis
Robert A
RA
Strey
Christoph W
CW
Foukas
Periklis G
PG
Gerard
Craig
C
Gerard
Norma
N
Wetsel
Rick A
RA
Lambris
John D
JD
D000818:Animals; D016923:Cell Death / Q000235:genetics / Q000276:immunology; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D003167:Complement Activation / Q000235:genetics / Q000276:immunology; D003176:Complement C3 / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D015926:Complement C3a / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D015936:Complement C5a / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D003165:Complement System Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D006498:Hepatectomy; D008099:Liver / Q000166:cytology* / Q000276:immunology*; D008115:Liver Regeneration / Q000235:genetics / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
D003176:Complement C3; D015926:Complement C3a; D015936:Complement C5a; D003165:Complement System Proteins