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

Dolore B. Njoku, Zhaoxia Li, Nicole D. Washington, Jenelle L. Mellerson, Monica V. Talor, Rajni Sharma, Noel R. Rose

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

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 DELI 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 naive 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 EFN-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.

Original languageEnglish
Pages (from-to)1652-1663
Number of pages12
JournalEuropean Journal of Immunology
Volume39
Issue number6
DOIs
StatePublished - 2009

Keywords

  • Cytochrome P450 2E1
  • Drug-induced liver injury
  • IL-4
  • Idiosyncratic acute liver failure
  • Trifluoroacetyl chloride

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