Suppressive and pro‐inflammatory roles for IL‐4 in the pathogenesis of experimental drug‐induced liver injury

The pathogenesis of immune‐mediated drug‐induced liver injury (DILI) following halogenated anesthetics, carbamazepine or alcohol has not been fully elucidated. Detecting cytochrome P450 2E1 (CYP2E1) IgG4 auto‐antibodies in anesthetic DILI patients suggests a role for IL‐4 in this hapten‐mediated process. We investigated IL‐4‐mediated mechanisms using our model of experimental DILI induced by immunizing BALB/c (WT) and IL‐4^?/? (KO) mice with S100 liver proteins covalently modified by a trifluoroacetyl chloride (TFA) hapten formed following halogenated anesthetic metabolism by CYP2E1. WT mice developed more hepatitis, TFA and S100 antibodies (p<0.01), as well as T‐cell proliferation to CYP2E1 and TFA (p<0.01) than KO mice. Additionally, WT CD4⁺ T cells adoptively transferred hepatitis to naïve Rag^?/? mice (p<0.01). Pro‐inflammatory cytokines were expectedly decreased in TFA hapten‐stimulated KO splenocyte supernatants (p<0.001); however, IL‐2 and IFN‐γ (p<0.05), as well as IL‐6 and IL‐10 (p<0.001) levels were elevated in CYP2E1‐stimulated KO splenocyte supernatants, suggesting dual IL‐4‐mediated pro‐inflammatory and regulatory responses. Anti‐IL‐10 administered to KO mice increased hepatitis, TFA and CYP2E1 antibodies in KO mice confirming a critical role for IL‐4. This is the first demonstration of dual roles for IL‐4 in the pathogenesis of immune‐mediated DILI by suppressing auto‐antigen‐induced regulatory responses while promoting hapten‐induced pro‐inflammatory responses.