We previously reported that interleukin (IL)-4 protects against susceptibility of mice to acetaminophen-induced liver injury (AILI), the leading cause of acute liver failure. The hepatoprotective effect of IL-4 was due at least in part to its induction of gamma-glutamylcysteine ligase (gamma-GCL), the rate determining enzyme in glutathione (GSH) synthesis, as IL-4 deficiency resulted in decreased mRNA and protein levels of gamma-GCL, prolonged depletion of GSH levels in the liver, and increased susceptibility to AILI. This year we discovered that the prolonged diminished levels of hepatic GSH seen in acetaminophen-treated IL-4 deficient mice contributed to the severity of AILI by causing continuous hepatic oxidative stress and resultant sustained activation of c-Jun-N-terminal kinase (JNK) signaling, which contributes to AILI by causing hepatic mitochondrial dysfunction. Conclusion: Overall these results are consistent with IL-4 having a previously unrecognized role in decreasing susceptibility to DILD by modulating hepatic GSH homeostasis and inhibiting conditions of excessive oxidative stress that can activate JNK signaling resulting in hepatocyte cell death. Moreover, it is possible that patients who are susceptible to DILD have polymorphisms in the IL-4 gene, the IL-4 receptor genes, and/or possibly the gamma-GCL genes that inhibit the hepatoprotective effects of IL-4.

Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2011
Total Cost
$495,446
Indirect Cost
Name
National Heart, Lung, and Blood Institute
Department
Type
DUNS #
City
State
Country
Zip Code
Masson, Mary Jane; Collins, Lindsay A; Pohl, Lance R (2010) The role of cytokines in the mechanism of adverse drug reactions. Handb Exp Pharmacol :195-231