Hepatoprotective Role of Endogenous Interleukin-13 in a Murine Model of Acetaminophen-Induced Liver Disease
ABSTRACT Recent evidence suggests that a deficiency in one or more hepatoprotective regulatory mechanisms may contribute to determining susceptibility in drug-induced liver disease. In the present study, we investigated the role of interleukin (IL)-13 in acetaminophen (APAP)-induced liver disease (AILD). Following APAP (200 mg/kg) administration to male C57BL/6 wild-type (WT) mice, hepatotoxicity developed up to 24 h post-APAP, with a concomitant increase in serum IL-13 concentration. Pretreatment of these mice with an IL-13-neutralizing antibody exacerbated liver injury, as did APAP administration to IL-13 knockout (KO) mice in comparison to WT mice. No difference was observed in either overall APAP-protein adduct formation or liver glutathione levels between KO and WT mice following APAP administration, suggesting that the increased susceptibility of IL-13 KO mice to AILD was not due to enhanced APAP bioactivation but rather injurious downstream events. In this regard, multiplex antibody arrays were used to identify potential IL-13-regulated biomarkers, including various cytokines and chemokines, as well as nitric oxide (NO), associated with AILD that were present at higher concentrations in the sera of APAP-treated IL-13 KO mice than in WT mice. Subsequent inhibition studies determined interferon-gamma, NO, neutrophils, natural killer cells, and natural killer cells with T-cell receptors had pathologic roles in AILD in IL-13 KO mice. Taken together, these results suggest that IL-13 is a critical hepatoprotective factor modulating the susceptibility to AILD and may provide hepatoprotection, in part, by down-regulating protoxicant factors and cells associated with the innate immune system.
- SourceAvailable from: Nan-Shih Liao
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- "Depletion or inactivation of KCs by chemicals in an AILI model had controversial results, with a protective effect in one study  but a negative result in another . Furthermore, mice lacking of cytokines such as interleukin 10 (IL-10) , IL-6  or IL-13  were found susceptible to APAP hepatotoxicity, whereas induction of pro-inflammatory mediators such as tumor necrosis factor alpha (TNFα) , interferon gamma (IFNγ) , IL-18 or IL-1β  and nitric oxide (NO) enhanced AILI in mice. Collectively, the roles of innate immune cells, especially antigen-presenting cells, and cytokines in AILI are complicated and still unclear. "
ABSTRACT: Hepatocytes have a direct necrotic role in acetaminophen (APAP)-induced liver injury (AILI), prolonged secondary inflammatory response through innate immune cells and cytokines also significantly contributes to APAP hepatotoxicity. Interleukin 15 (IL-15), a multifunction cytokine, regulates the adaptive immune system and influences development and function of innate immune cells. To better understand the role of IL-15 in liver injury, we treated wild-type (WT) and IL-15-knockout (Il15(-/-)) mice with a hepatotoxic dose of APAP to induce AILI and evaluated animal survival, liver damage, APAP metabolism in livers and the inflammatory response. Production of pro-inflammatory cytokines/chemokines was greater in Il15(-/-) than WT mice. Subanalysis of hepatic infiltrated monocytes revealed greater neutrophil influx, along with greater hepatic induction of inducible nitric oxide synthase (iNOS), in Il15(-/-) than WT mice. In addition, the level of hepatic hemeoxygenase 1 (HO-1) was partially suppressed in Il15(-/-) mice, but not in WT mice. Interestingly, elimination of Kupffer cells and neutrophils did not alter the vulnerability to excess APAP in Il15(-/-) mice. However, injection of galactosamine, a hepatic transcription inhibitor, significantly reduced the increased APAP sensitivity in Il15(-/-) mice but had minor effect on WT mice. We demonstrated that deficiency of IL-15 increased mouse susceptibility to AILI. Moreover, Kupffer cell might affect APAP hepatotoxicity through IL-15.PLoS ONE 09/2012; 7(9):e44880. DOI:10.1371/journal.pone.0044880 · 3.23 Impact Factor
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- "Pretreatment of mice with IL-13 reduced acetaminophen toxicity-and IL-13 knockout mice were sensitive to the toxic effects of acetaminophen. In further studies, IL-13 was shown to modulate IFN-γ, nitric oxide, and inflammatory cells, including neutrophils, NK cells, and NKT cells (Yee et al. 2007). A recent study examined acetaminophen toxicity in two strains of mice that had distinct inflammatory and cytokine profiles (Cover et al. 2006). "
ABSTRACT: Although considered safe at therapeutic doses, at higher doses, acetaminophen produces a centrilobular hepatic necrosis that can be fatal. Acetaminophen poisoning accounts for approximately one-half of all cases of acute liver failure in the United States and Great Britain today. The mechanism occurs by a complex sequence of events. These events include: (1) CYP metabolism to a reactive metabolite which depletes glutathione and covalently binds to proteins; (2) loss of glutathione with an increased formation of reactive oxygen and nitrogen species in hepatocytes undergoing necrotic changes; (3) increased oxidative stress, associated with alterations in calcium homeostasis and initiation of signal transduction responses, causing mitochondrial permeability transition; (4) mitochondrial permeability transition occurring with additional oxidative stress, loss of mitochondrial membrane potential, and loss of the ability of the mitochondria to synthesize ATP; and (5) loss of ATP which leads to necrosis. Associated with these essential events there appear to be a number of inflammatory mediators such as certain cytokines and chemokines that can modify the toxicity. Some have been shown to alter oxidative stress, but the relationship of these modulators to other critical mechanistic events has not been well delineated. In addition, existing data support the involvement of cytokines, chemokines, and growth factors in the initiation of regenerative processes leading to the reestablishment of hepatic structure and function.Handbook of experimental pharmacology 01/2010; 196(196):369-405. DOI:10.1007/978-3-642-00663-0_12
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- "The molecular mechanisms of action of acetaminophen are controversial and still poorly understood (Tripathy and Grammas 2009a). The possible pro-and antiinflammatory actions of acetaminophen are complex because high acetaminophen administration initiates a series of both pro-and anti-inflammatory cascades (Yee et al. 2007). It is likely that there are other, as yet unidentified physiological targets for both the toxic and therapeutic actions of acetaminophen. "
ABSTRACT: Acetaminophen, an analgesic and antipyretic drug, rescues neuronal cells from mitochondrial redox impairment and reactive oxygen species (ROS). Excessive administration of acetaminophen above the recommended daily dose range has some negative effects on the brain. We investigated the effects of different doses of acetaminophen on Ca(2+)-ATPase and the antioxidant redox system in rats. Seventy rats were randomly divided into seven equal groups. The first was used for the control. One dose of 5, 10, 20, 100, 200, and 500 mg/kg acetaminophen was intraperitoneally administered to rats constituting the second, third, fourth, fifth, sixth, and seventh groups, respectively. After 24 h, brain cortical samples were taken and brain microsomal samples were obtained by ultracentrifugation. Brain and microsomal lipid peroxidation (LP) and brain calcium levels in the sixth and seventh groups were increased compared to control. LP levels in the second, third, and forth groups; brain vitamin E levels; brain and microsomal glutathione peroxidase (GSH-Px); and Ca(2+)-ATPase activity in the sixth and seventh groups were lower than in control, although brain vitamin E concentrations in the second, third, fourth, and fifth groups and microsomal GSH-Px activity in the third and fourth groups were higher than in control. Brain cortical beta-carotene and vitamin A concentrations did not differ in the seven groups. In conclusion, 5-100 mg/kg acetaminophen seems to have protective effects on oxidative stress-induced brain toxicity by inhibiting free radicals and supporting the antioxidant redox system.Journal of Membrane Biology 10/2009; 231(2-3):57-64. DOI:10.1007/s00232-009-9203-3 · 2.46 Impact Factor