The role of complement activation in tumour necrosis factor-induced lethal hepatitis

Cytokine. 1999 Aug;11(8):617-25. doi: 10.1006/cyto.1998.0462.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Chemical and Drug Induced Liver Injury / immunology*
  • Chemical and Drug Induced Liver Injury / pathology
  • Chemical and Drug Induced Liver Injury / prevention & control
  • Complement Activation / drug effects
  • Complement Activation / immunology*
  • Complement C1q / analysis
  • Complement C3b / analysis
  • Complement Pathway, Alternative / immunology
  • Complement Pathway, Classical / immunology
  • Elapid Venoms / pharmacology
  • Female
  • Galactosamine / toxicity
  • Liver / drug effects
  • Liver / immunology*
  • Liver / pathology
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Inbred CBA
  • Tumor Necrosis Factor-alpha / toxicity*


  • Elapid Venoms
  • Tumor Necrosis Factor-alpha
  • cobra venom factor
  • Galactosamine
  • Complement C1q
  • Complement C3b