The role of complement activation in tumour necrosis factor-induced lethal hepatitis.
Injection of tumour necrosis factor (TNF) in animals causes severe liver cell toxicity, especially when D-(+)-galactosamine (GalN) is co-administered. After challenge with TNF/GalN, serum complement activity (CH50 and APCH50) decreased dramatically, suggesting strong activation of both the classical and the alternative pathways. TNF or GalN alone had no such effect. A cleavage product of complement protein C3 [C3(b)] was deposited on the surface of hepatocytes of TNF/GalN-treated mice. Intravenous administration of cobra venom factor (CVF), which depletes complement, inhibited the development of hepatitis. However, CVF pretreatment also protected C3-deficient mice. Pretreatment of mice with a C1q-depleting antibody did not prevent TNF/GalN lethality, although the anti-C1q antibody had depleted plasma C1q. Factor B-deficient and C3-deficient mice, generated by gene targeting, proved to be as sensitive to TNF/GalN as control mice. Furthermore, induction of lethal shock by platelet-activating factor, an important mediator in TNF-induced hepatic failure, was not reduced in C3-deficient mice. These data indicate that complement, although activated, plays no major role in the generation of acute lethal hepatic failure in this model and that CVF-induced protection is independent of complement depletion.
Libert
C
C
Department of Molecular Biology, Flanders Interuniversity Institute for Biotechnology and University of Ghent, K.L. Ledeganckstraat 35, Ghent, B-9000, Belgium.
Wielockx
B
B
Grijalba
B
B
Van Molle
W
W
Kremmer
E
E
Colten
H R
HR
Fiers
W
W
Brouckaert
P
P
D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D003167:Complement Activation / Q000187:drug effects / Q000276:immunology*; D015922:Complement C1q / Q000032:analysis; D003179:Complement C3b / Q000032:analysis; D003170:Complement Pathway, Alternative / Q000276:immunology; D003171:Complement Pathway, Classical / Q000276:immunology; D004546:Elapid Venoms / Q000494:pharmacology; D005260:Female; D005688:Galactosamine / Q000633:toxicity; D008099:Liver / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D014409:Tumor Necrosis Factor-alpha / Q000633:toxicity*
D004546:Elapid Venoms; D014409:Tumor Necrosis Factor-alpha; C016310:cobra venom factor; D005688:Galactosamine; D015922:Complement C1q; D003179:Complement C3b