Role of IL-6 in an IL-10 and IL-4 double knockout mouse model uniquely susceptible to acetaminophen-induced liver injury.
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.
Bourdi
Mohammed
M
Molecular and Cellular Toxicology Section, Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland 20892, USA. bourdim@nih.gov
Eiras
Daniel P
DP
Holt
Michael P
MP
Webster
Marie R
MR
Reilly
Timothy P
TP
Welch
Kevin D
KD
Pohl
Lance R
LR
D000082:Acetaminophen / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001119:Arginase / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D015415:Biomarkers / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease; D005978:Glutathione / Q000187:drug effects / Q000378:metabolism; D007372:Interferons / Q000096:biosynthesis; D016753:Interleukin-10 / Q000172:deficiency* / Q000235:genetics; D015847:Interleukin-4 / Q000172:deficiency* / Q000235:genetics; D015850:Interleukin-6 / Q000097:blood / Q000502:physiology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000096:biosynthesis / Q000097:blood; D000093242:Interleukin-6 Inhibitors
D000082:Acetaminophen; D000906:Antibodies; D001119:Arginase; D015415:Biomarkers; D005978:Glutathione; D007372:Interferons; D016753:Interleukin-10; D015847:Interleukin-4; D015850:Interleukin-6; D009569:Nitric Oxide; D000093242:Interleukin-6 Inhibitors