Clinical immunology

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

  1. Dolores B. Njoku1,2,3,*,
  2. Zhaoxia Li1,
  3. Nicole D. Washington2,
  4. Jenelle L. Mellerson3,
  5. Monica V. Talor3,
  6. Rajni Sharma3,
  7. Noel R. Rose3,4

Article first published online: 4 JUN 2009

DOI: 10.1002/eji.200838135

Issue

European Journal of Immunology

European Journal of Immunology

Volume 39, Issue 6, pages 1652–1663, June 2009

Additional Information

How to Cite

Njoku, D. B., Li, Z., Washington, N. D., Mellerson, J. L., Talor, M. V., Sharma, R. and Rose, N. R. (2009), Suppressive and pro-inflammatory roles for IL-4 in the pathogenesis of experimental drug-induced liver injury. Eur. J. Immunol., 39: 1652–1663. doi: 10.1002/eji.200838135

Author Information

  1. 1

    Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins Medical Institutions, Baltimore, MD, USA

  2. 2

    Department of Pediatrics, The Johns Hopkins Medical Institutions, Baltimore, MD, USA

  3. 3

    Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, MD, USA

  4. 4

    W. Harvey Feinstone Department of Molecular Microbiology and Immunology, The Johns Hopkins Medical Institutions, Baltimore, MD, USA

*Departments of Anesthesiology and Critical Care Medicine, Pediatrics and Pathology, Johns Hopkins Medical Institutions, 600 North Wolfe Street, Blalock 906A, Baltimore, MD 21287, USA Fax: +1-410-502-5312

Publication History

  1. Issue published online: 4 JUN 2009
  2. Article first published online: 4 JUN 2009
  3. Manuscript Accepted: 31 MAR 2009
  4. Manuscript Revised: 12 FEB 2009
  5. Manuscript Received: 2 JAN 2008

Funded by

  • Unknown funding agency. Grant Number: NIHR21DK075828
  • American Autoimmune Related Diseases Association
  • The Gail I Zuckerman Foundation

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Keywords:

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

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-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.

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