Sex Bias in Experimental Immune-Mediated, Drug-Induced Liver Injury in BALB-c Mice: Suggested Roles for Tregs, Estrogen, and IL-6Reportar como inadecuado

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Background and Aims

Immune-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.


To 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.


BALB-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.


17β-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.

Autor: Joonhee Cho, Lina Kim, Zhaoxia Li, Noel R. Rose, Monica Vladut Talor, Dolores B. Njoku



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