title: Endogenous interleukin-4 regulates glutathione synthesis following acetaminophen-induced liver injury in mice.
abstract: In a recent study, we reported that interleukin (IL)-4 had a protective role against acetaminophen (APAP)-induced liver injury (AILI), although the mechanism of protection was unclear. Here, we carried out more detailed investigations and have shown that one way IL-4 may control the severity of AILI is by regulating glutathione (GSH) synthesis. In the present studies, the protective role of IL-4 in AILI was established definitively by showing that C57BL/6J mice made deficient in IL-4 genetically (IL-4(-/-)) or by depletion with an antibody, were more susceptible to AILI than mice not depleted of IL-4. The increased susceptibility of IL-4(-/-) mice was not due to elevated levels of hepatic APAP-protein adducts but was associated with a prolonged reduction in hepatic GSH that was attributed to decreased gene expression of γ-glutamylcysteine ligase (γ-GCL). Moreover, administration of recombinant IL-4 to IL-4(-/-) mice postacetaminophen treatment diminished the severity of liver injury and increased γ-GCL and GSH levels. We also report that the prolonged reduction of GSH in APAP-treated IL-4(-/-) mice appeared to contribute toward increased liver injury by causing a sustained activation of c-Jun-N-terminal kinase (JNK) since levels of phosphorylated JNK remained significantly higher in the IL-4(-/-) mice up to 24 h after APAP treatment. Overall, these results show for the first time that IL-4 has a role in regulating the synthesis of GSH in the liver under conditions of cellular stress. This mechanism appears to be responsible at least in part for the protective role of IL-4 against AILI in mice and may have a similar role not only in AILI in humans but also in pathologies of the liver caused by other drugs and etiologies.
authors: Molecular and Cellular Toxicology Section, Laboratory of Molecular Immunology, Immunology Center, National Heart, Lung and Blood Institute,  National Institutes of Health , 9000 Rockville Pike, Building 10, Room 8N110, Bethesda, Maryland 20892, United States.
authors: Pauline M
authors: PM
authors: Ryan
authors: Mohammed
authors: M
authors: Bourdi
authors: Midhun C
authors: MC
authors: Korrapati
authors: William R
authors: WR
authors: Proctor
authors: Ronald A
authors: RA
authors: Vasquez
authors: Steven B
authors: SB
authors: Yee
authors: Timothy D
authors: TD
authors: Quinn
authors: Mala
authors: M
authors: Chakraborty
authors: Lance R
authors: LR
authors: Pohl
mesh_terms: D000082:Acetaminophen / Q000633:toxicity*; D018712:Analgesics, Non-Narcotic / Q000633:toxicity*; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism* / Q000473:pathology; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D005721:Glutamate-Cysteine Ligase / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism*; D015847:Interleukin-4 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000378:metabolism
chemical_list: D018712:Analgesics, Non-Narcotic; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D015847:Interleukin-4; D000082:Acetaminophen; D019392:Cytochrome P-450 CYP2E1; D048031:JNK Mitogen-Activated Protein Kinases; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione