Increased toxin-induced liver injury and fibrosis in interleukin-6-deficient mice

Hepatology. 2000 Jan;31(1):149-59. doi: 10.1002/hep.510310123.

Abstract

Interleukin-6 null (IL-6-/-) mice have impaired liver regeneration and increased liver necrosis following partial hepatectomy that is corrected with IL-6 treatment. Following acute carbon tetrachloride (CCl(4)) treatment, we found that IL-6-/- mice developed increased hepatocellular injury and defective regeneration with significant blunting of signal transducer-and-activator of transcription protein 3 (STAT3) and nuclear factor-kappaB (NF-kappaB) activation and reduced hepatocyte DNA synthetic and mitotic responses. After CCl(4) treatment, unlike partial hepatectomy, increased hepatocyte apoptosis was noted in IL-6-/- livers. Pretreatment with IL-6 before CCl(4) reduced acute CCl(4) injury and apoptosis and accelerated regeneration in both IL-6+/+ and -/- livers. Repetitive doses of CCl(4) in the presence or absence of phenobarbital resulted in increased injury and fibrosis in IL-6 -/- compared with +/+ livers. After acute and chronic injury, IL-6-/- livers showed the protracted presence of alpha-smooth muscle actin associated with activated stellate cells, indicating a disturbed response in wound healing that progressed to fibrosis. These data provide evidence for an important role for IL-6 in reducing CCl(4)-induced acute and chronic liver injury and fibrosis.

Publication types

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

MeSH terms

  • Actins / metabolism
  • Animals
  • Apoptosis
  • Carbon Tetrachloride
  • Chemical and Drug Induced Liver Injury*
  • DNA / biosynthesis
  • DNA-Binding Proteins / metabolism
  • Interleukin-6 / deficiency*
  • Interleukin-6 / physiology
  • Kinetics
  • Liver Cirrhosis, Experimental / chemically induced*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitosis
  • NF-kappa B / metabolism
  • Phenobarbital / administration & dosage
  • STAT3 Transcription Factor
  • Trans-Activators / metabolism

Substances

  • Actins
  • DNA-Binding Proteins
  • Interleukin-6
  • NF-kappa B
  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • Trans-Activators
  • DNA
  • Carbon Tetrachloride
  • Phenobarbital