Interleukin-4 deficiency protects mice from acetaminophen-induced liver injury and inflammation by prevention of glutathione depletion
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Interleukin-4 (IL-4) is a multifunctional cytokine involved in many diseases such as autoimmune hepatitis and idiosyncratic drug reactions. However, its role in acetaminophen (APAP)-induced liver injury remains unclear. Our objective was to evaluate the contribution of IL-4 to the pathogenesis of APAP-induced liver injury.
Balb/C (WT) and IL-4 knockout (IL-4−/−) mice were orally overdosed with APAP. After 24 h, survival percentage, biochemical and morphological markers of liver injury, and tissue inflammation were assessed.
IL-4−/− mice were protected from APAP toxicity. Intravital confocal microscopy, tissue histology and serum ALT levels showed significantly less liver injury and inflammation than in the WT group, which may explain the increased survival rate of IL-4−/− mice. In addition, IL-4−/− mice had decreased production of tumor necrosis factor α, CXCL1 and interleukin-1β in the liver, but not in a remote site such as the lungs. Hepatic macrophage activation was markedly reduced in IL-4-deficient mice. In addition, glutathione depletion—a primary cause of APAP-mediated injury—was significantly attenuated in IL-4−/− mice.
Taken together, our data demonstrate that IL-4−/− mice are protected from APAP-induced liver injury due to reduced depletion of glutathione, which prevented liver damage and tissue inflammation.
KeywordsInterleukin-4 Liver injury Acetaminophen Glutathione
This study was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Fundação de Amparo à Pesquisa do estado de Minas Gerais (FAPEMIG/PRONEX), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES).
Conflict of interest
The authors do not have any conflict of interests to disclose.
Online Resource 2. 3D reconstruction of a liver from a control mouse undergoing confocal intravital microscopy. The hepatic vasculature is labeled by FITC-albumin (green) and the liver cells by Rhodamine 6G (red) (MPG 1546 kb)
Online Resource 3. 3D reconstruction of a liver from an APAP-overdosed wild-type mouse undergoing confocal intravital microscopy. The hepatic vasculature is labeled by FITC-albumin (green) and the liver cells by Rhodamine 6G (red) (MPG 1490 kb)
Online Resource 4. 3D reconstruction of a liver from an APAP-overdosed IL-4 knockout mouse undergoing confocal intravital microscopy. The hepatic vasculature is labeled by FITC-albumin (green) and the liver cells by Rhodamine 6G (red) (MPG 1434 kb)
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