PMID- 17305405
OWN - NLM
STAT- MEDLINE
DCOM- 20070515
LR  - 20220330
IS  - 0893-228X (Print)
IS  - 0893-228X (Linking)
VI  - 20
IP  - 2
DP  - 2007 Feb
TI  - Role of IL-6 in an IL-10 and IL-4 double knockout mouse model uniquely 
      susceptible to acetaminophen-induced liver injury.
PG  - 208-16
AB  - 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.
FAU - Bourdi, Mohammed
AU  - Bourdi M
AD  - 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
FAU - Eiras, Daniel P
AU  - Eiras DP
FAU - Holt, Michael P
AU  - Holt MP
FAU - Webster, Marie R
AU  - Webster MR
FAU - Reilly, Timothy P
AU  - Reilly TP
FAU - Welch, Kevin D
AU  - Welch KD
FAU - Pohl, Lance R
AU  - Pohl LR
LA  - eng
GR  - Intramural NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Intramural
PL  - United States
TA  - Chem Res Toxicol
JT  - Chemical research in toxicology
JID - 8807448
RN  - 0 (Antibodies)
RN  - 0 (Biomarkers)
RN  - 0 (Interleukin-6)
RN  - 130068-27-8 (Interleukin-10)
RN  - 207137-56-2 (Interleukin-4)
RN  - 31C4KY9ESH (Nitric Oxide)
RN  - 362O9ITL9D (Acetaminophen)
RN  - 9008-11-1 (Interferons)
RN  - EC 3.5.3.1 (Arginase)
RN  - GAN16C9B8O (Glutathione)
SB  - IM
MH  - Acetaminophen/administration & dosage/*toxicity
MH  - Animals
MH  - Antibodies/pharmacology
MH  - Arginase/antagonists & inhibitors/biosynthesis
MH  - Biomarkers/blood
MH  - Chemical and Drug Induced Liver Injury/blood/*metabolism/pathology
MH  - *Disease Models, Animal
MH  - Genetic Predisposition to Disease
MH  - Glutathione/drug effects/metabolism
MH  - Interferons/biosynthesis
MH  - Interleukin-10/*deficiency/genetics
MH  - Interleukin-4/*deficiency/genetics
MH  - Interleukin-6/antagonists & inhibitors/blood/*physiology
MH  - Liver/drug effects/metabolism/pathology
MH  - Mice
MH  - Mice, Knockout
MH  - Nitric Oxide/biosynthesis/blood
EDAT- 2007/02/20 09:00
MHDA- 2007/05/16 09:00
CRDT- 2007/02/20 09:00
PHST- 2007/02/20 09:00 [pubmed]
PHST- 2007/05/16 09:00 [medline]
PHST- 2007/02/20 09:00 [entrez]
AID - 10.1021/tx060228l [doi]
PST - ppublish
SO  - Chem Res Toxicol. 2007 Feb;20(2):208-16. doi: 10.1021/tx060228l.