Protection against acetaminophen-induced liver injury and lethality by interleukin 10: Role of inducible nitric oxide synthase

Abstract

Mechanistic study of idiosyncratic drug-induced hepatitis (DIH) continues to be a challenging problem because of the lack of animal models. The inability to produce this type of hepatotoxicity in animals, and its relative rarity in humans, may be linked to the production of antiinflammatory factors that prevent drug-protein adducts from causing liver injury by immune and nonimmune mechanisms. We tested this hypothesis by using a model of acetaminophen (APAP)-induced liver injury in mice. After APAP treatment, a significant increase was observed in serum levels of interleukin (IL)-4, IL-10, and IL-13, cytokines that regulate inflammatory mediator production and cell-mediated autoimmunity. When IL-10 knockout (KO) mice were treated with APAP, most of these mice died within 24 to 48 hours from liver injury. This increased susceptibility to APAP-induced liver injury appeared to correlate with an elevated expression of liver proinflammatory cytokines, tumor necrosis factor (TNF)-␣, and IL-1, as well as inducible nitric oxide synthase (iNOS). In this regard, mice lacking both IL-10 and iNOS genes were protected from APAP-induced liver injury and lethality when compared with IL-10 KO mice. All strains, including wild-type animals, generated similar amounts of liver APAPprotein adducts, indicating that the increased susceptibility of IL-10 KO mice to APAP hepatotoxicity was not caused by an enhanced formation of APAP-protein adducts. Epidemiologic studies reveal that as many as 25% of fulminant hepatitis cases in intensive care units are caused by DIH. 1 It is also the major reason for removal of new drugs from clinical development and widespread use. 2 Although DIH can be very severe, the incidence for any given drug is usually low. It has been hypothesized that this idiosyncratic nature of DIH is either caused by a metabolic idiosyncrasy, in which patients who develop toxicity metabolize the drug to reactive metabolites to a greater extent than most others, 3 or an immunologic idiosyncrasy (druginduced allergic hepatitis [DIAH]), in which the immune system of patients who develop DIH react against protein adducts of drugs or other neoantigens formed in the liver. 3,4 These 2 mechanisms are not mutually exclusive and might both contribute to the initiation of DIH. 3 However, the demonstration of specific antibodies and sensitized T cells that react with drugs, their metabolites, or specific protein neoantigens and/or autoantigens supports the immunologic basis of DIH. [2][3][4][5][6] The host-dependent, idiosyncratic nature of DIH is poorly understood, but may be related to a variety of factors that in most individuals either fail to promote or, in fact, protect against DIH. For example, genetic polymorphisms in the specific repertoire of major histocompatibility complex class I and II antigens and/or Band T-cell receptors may render the immune cells from most individuals incapable of satisfactorily binding or presenting protein adducts of drugs or their derived peptides and, therefore, unable to lead to immunopatholog...

Hepatic adducts, circulating antibodies, and cytokine polymorphisms in patients with diclofenac hepatotoxicity

“…Polymorphisms in the major histocompatibility complex molecules have previously been shown to modify susceptibility to drug-induced hepatotoxicity as they determine the efficient presentation of alkylated immunogenic peptides. 38 Associations have been reported between HLA11 and diclofenac hepatotoxicity, which is consistent with an important role for the immune system in determining susceptibility to this disease. 39 The current observations are based on relatively small groups and need to be confirmed in a larger study, but they point to the possibility of identifying individuals who may be at increased risk of adverse drug reactions by genotyping for immune system polymorphisms.…”

“…In addition, the anti-inflammatory (rather than the immunoregulatory) properties of IL-10 might be important in drug-induced liver injury 15 as demonstrated by the susceptibility of IL-10 "knockout" mice to acetaminophen-induced hepatotoxicity. 38 Therefore, the association of cytokine polymorphisms with diclofenac hepatotoxicity demonstrated in this study may be independent of the immune mechanisms described.…”

Reduced acetaminophen-induced liver injury in mice by genetic disruption of IL-1 receptor antagonist

“…[34][35][36] These observations would indicate the essential involvement of inflammatory responses in the development of liver damages caused by APAP. Accumulating evidence implicates IL-1a and IL-1b as crucial mediators in various inflammatory reaction 11,[13][14][15] and their endogenous antagonist, IL-1ra, can inhibit the biological activities of IL-1s by competitive binding to IL-1RI.…”

“…By contrast, there was no significant difference in the intrahepatic expression of IL-6 and IL-10, the cytokines that had protective roles in APAP-induced liver injury (data not shown). 34,35 These observations would imply that impaired NAPQI generation in IL-1ra KO mice reduced the initiation of APAP-induced liver injury and subsequent inflammatory reactions as evidenced by reduced IL-1 and chemokine expression.…”

Heme Oxygenase-1 Couples Activation of Mitochondrial Biogenesis to Anti-inflammatory Cytokine Expression

“…Free heme is cytotoxic, and heme clearance reduces oxidative stress and apoptosis (58), which is assumed to promote resolution of inflammation. IL-10 attenuates the host response to microbial antigens, to cytokines and chemokines (21,59), to ischemia reperfusion, and to some drug-induced injuries (13,60). This limits tissue damage, but the persistence of IL-10 leads to immune suppression and to impaired pathogen clearance in infection (61).…”