Abstract
Background and AimsImmune-mediated, drug-induced liver injury (DILI) triggered by drug haptens is more prevalent in women than in men. However, mechanisms responsible for this sex bias are not clear. Immune regulation by CD4+CD25+FoxP3+ regulatory T-cells (Tregs) and 17β-estradiol is crucial in the pathogenesis of sex bias in cancer and autoimmunity. Therefore, we investigated their role in a mouse model of immune-mediated DILI.MethodsTo model DILI, we immunized BALB/c, BALB/cBy, IL-6–deficient, and castrated BALB/c mice with trifluoroacetyl chloride-haptenated liver proteins. We then measured degree of hepatitis, cytokines, antibodies, and Treg and splenocyte function.ResultsBALB/c females developed more severe hepatitis (p<0.01) and produced more pro-inflammatory hepatic cytokines and antibodies (p<0.05) than did males. Castrated males developed more severe hepatitis than did intact males (p<0.001) and females (p<0.05). Splenocytes cultured from female mice exhibited fewer Tregs (p<0.01) and higher IL-1β (p<0.01) and IL-6 (p<0.05) than did those from males. However, Treg function did not differ by sex, as evidenced by absence of sex bias in programmed death receptor-1 and responses to IL-6, anti-IL-10, anti-CD3, and anti-CD28. Diminished hepatitis in IL-6-deficient, anti-IL-6 receptor α-treated, ovariectomized, or male mice; undetectable IL-6 levels in splenocyte supernatants from ovariectomized and male mice; elevated splenic IL-6 and serum estrogen levels in castrated male mice, and IL-6 induction by 17β-estradiol in splenocytes from naïve female mice (p<0.05) suggested that 17β-estradiol may enhance sex bias through IL-6 induction, which subsequently discourages Treg survival. Treg transfer from naïve female mice to those with DILI reduced hepatitis severity and hepatic IL-6.Conclusions17β-estradiol and IL-6 may act synergistically to promote sex bias in experimental DILI by reducing Tregs. Modulating Treg numbers may provide a therapeutic approach to DILI.
Highlights
Drug-induced liver injury (DILI) accounts for more than 50% of all cases of acute liver failure
drug-induced liver injury (DILI) induced by halogenated volatile anesthetics such as isoflurane, desflurane, or halothane is triggered by neoantigens that are produced when native liver proteins such as cytochrome p450 2E1 (CYP2E1) become covalently modified by trifluroacetyl chloride (TFA) haptens, which are formed by CYP2E1 oxidative anesthetic metabolism [1,2,3,4]
We show that sex bias in the severity of experimental anesthetic DILI is driven by a reduction in the number of Tregs and that this reduction may be induced by pro-inflammatory cytokines such as interleukin (IL)-6 that have been up-regulated by estrogen
Summary
Drug-induced liver injury (DILI) accounts for more than 50% of all cases of acute liver failure. DILI induced by halogenated volatile anesthetics such as isoflurane, desflurane, or halothane is triggered by neoantigens that are produced when native liver proteins such as cytochrome p450 2E1 (CYP2E1) become covalently modified by trifluroacetyl chloride (TFA) haptens, which are formed by CYP2E1 oxidative anesthetic metabolism [1,2,3,4]. Complex immune responses to these neoantigens induce hepatitis and production of antibodies to native proteins and drug haptens. Experimental anesthetic DILI is characterized by a splenic priming phase that occurs 2 weeks after immunization with S100 liver proteins that are covalently altered by TFA haptens (TFAS100). Immune regulation by CD4+CD25+FoxP3+ regulatory T-cells (Tregs) and 17b-estradiol is crucial in the pathogenesis of sex bias in cancer and autoimmunity. We investigated their role in a mouse model of immune-mediated DILI
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