The role of complement activation in tumour necrosis factor-induced lethalhepatitis

injection of tumour necrosis factor (TNF) in animals causes severe liver ce ll 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 clea vage product of complement protein C3 [C3(b)] was deposited on the surface of hepatocytes of TNF/GalN-treated mice, Intravenous administration of cobr a venom factor (CVF), which depletes complement, inhibited the development of hepatitis, However, CVF pretreatment also protected C3-deficient mice. P retreatment 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 protecti on is independent of complement depletion. (C) 1999 Academic Press.