title: Suppressive and pro-inflammatory roles for IL-4 in the pathogenesis of experimental drug-induced liver injury.
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 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-gamma (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.
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins Medical Institutions, Baltimore, MD 21287, USA. dnjoku1@jhmi.edu
authors.forename: Dolores B
authors.initials: DB
authors.lastname: Njoku
authors.forename: Zhaoxia
authors.initials: Z
authors.lastname: Li
authors.forename: Nicole D
authors.initials: ND
authors.lastname: Washington
authors.forename: Jenelle L
authors.initials: JL
authors.lastname: Mellerson
authors.forename: Monica V
authors.initials: MV
authors.lastname: Talor
authors.forename: Rajni
authors.initials: R
authors.lastname: Sharma
authors.forename: Noel R
authors.initials: NR
authors.lastname: Rose
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000906:Antibodies / Q000097:blood / Q000276:immunology / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000637:transplantation; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000276:immunology* / Q000473:pathology; D019392:Cytochrome P-450 CYP2E1 / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005463:Fluoroacetates; D018398:Homeodomain Proteins / Q000235:genetics; D016753:Interleukin-10 / Q000037:antagonists & inhibitors / Q000276:immunology; D015847:Interleukin-4 / Q000276:immunology*; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D018448:Models, Immunological; D055611:Natural Killer T-Cells / Q000166:cytology / Q000276:immunology; D009418:S100 Proteins / Q000276:immunology; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism; D014269:Trifluoroacetic Acid / Q000276:immunology
chemical_list: D000906:Antibodies; D016207:Cytokines; D005463:Fluoroacetates; D018398:Homeodomain Proteins; D009418:S100 Proteins; C064658:RAG-1 protein; D016753:Interleukin-10; D015847:Interleukin-4; C500395:trifluoroacetyl chloride; D014269:Trifluoroacetic Acid; D019392:Cytochrome P-450 CYP2E1