Role of IL-6 in an IL-10 and IL-4 double knockout mouse model uniquely susceptible to acetaminophen-induced liver injury

Chem Res Toxicol. 2007 Feb;20(2):208-16. doi: 10.1021/tx060228l.

Abstract

Drug-induced hepatitis remains a challenging problem for drug development and safety because of the lack of animal models. In the current work, we discovered a unique interaction that makes mice deficient in both IL-10 and IL-4 (IL-10/4-/-) highly sensitive to the hepatotoxic effects of acetaminophen (APAP). Male C57Bl/6 wild type (WT) and mice deficient in one or more cytokines were treated with 120 mg/kg APAP. Within 24 h after WT, IL-10-/-, IL-4-/-, or IL-10/4-/- mice were administered APAP, 75% of the IL-10/4-/- mice died of massive hepatic injury while all other genotypes were resistant to liver toxicity at this dose of APAP. The unique susceptibility of IL-10/4-/- mice was associated with reduced levels of liver glutathione and remarkably high serum levels of IL-6 and several proinflammatory factors including TNF-alpha, IFN-gamma, macrophage inflammatory protein-1alpha (MIP-1alpha), monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein-2 (MIP-2), and osteopontin (OPN) as well as nitric oxide (NO). IL-6 appeared to have a causal role in controlling the unique susceptibility of IL-10/4-/- mice to APAP-induced liver disease (AILD) because IL-6 neutralizing antibody reversed the high sensitivity of these mice to AILD. Moreover, IL-10/4/6-/- mice were also resistant to the enhanced susceptibility to AILD and expressed relatively low levels of most proinflammatory factor genes that were elevated in the IL-10/4-/- mice. In conclusion, liver homeostasis following AILD appears to be highly dependent on the activities of both IL-10 and IL-4, which together help prevent overexpression of IL-6 and other potential hepatotoxic factors.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Acetaminophen / administration & dosage
  • Acetaminophen / toxicity*
  • Animals
  • Antibodies / pharmacology
  • Arginase / antagonists & inhibitors
  • Arginase / biosynthesis
  • Biomarkers / blood
  • Chemical and Drug Induced Liver Injury / blood
  • Chemical and Drug Induced Liver Injury / metabolism*
  • Chemical and Drug Induced Liver Injury / pathology
  • Disease Models, Animal*
  • Genetic Predisposition to Disease
  • Glutathione / drug effects
  • Glutathione / metabolism
  • Interferons / biosynthesis
  • Interleukin-10 / deficiency*
  • Interleukin-10 / genetics
  • Interleukin-4 / deficiency*
  • Interleukin-4 / genetics
  • Interleukin-6 / antagonists & inhibitors
  • Interleukin-6 / blood
  • Interleukin-6 / physiology*
  • Liver / drug effects
  • Liver / metabolism
  • Liver / pathology
  • Mice
  • Mice, Knockout
  • Nitric Oxide / biosynthesis
  • Nitric Oxide / blood

Substances

  • Antibodies
  • Biomarkers
  • Interleukin-6
  • Interleukin-10
  • Interleukin-4
  • Nitric Oxide
  • Acetaminophen
  • Interferons
  • Arginase
  • Glutathione