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In drug-induced, immune-mediated hepatitis, interleukin-33 reduces hepatitis and improves survival independently and as a consequence of FoxP3+ T-cell activity

Cellular & Molecular Immunology (2018) | Download Citation

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Immune-mediated, drug-induced hepatitis is a rare complication of halogenated volatile anesthetic administration. IL-4-regulated Th2-polarized reactions initiate this type and other types of hepatitis, while the mechanisms that regulate the severity remain elusive. IL-33 is an innate, IL-4-inducing, Th2-polarizing cytokine that has been detected in patients with liver failure and has been associated with upregulated ST2+Foxp3+CD4+CD25+ T cells; however, roles for IL-33 in drug-induced hepatitis are unclear. We investigated IL-33 in an anesthetic, immune-mediated hepatitis modeled in BALB/c, IL-33−/− and ST2−/− mice, as well as in patients with anesthetic hepatitis. The hepatic IL-33 and ST2 levels were elevated in BALB/c mice (p < 0.05) with hepatitis, and anti-IL-33 diminished hepatitis (p < 0.05) without reducing IL-33 levels. The complete absence of IL-33 reduced IL-10 (p < 0.05) and ST2+Foxp3+CD4+CD25+ T cells (p < 0.05), as well as reduced the overall survival (p < 0.05), suggesting suppressive roles for IL-33 in anesthetic, immune-mediated hepatitis. All of the mice demonstrated similar levels of CD4+ T-cell proliferation following direct T-cell receptor stimulation, but we detected splenic IL-33 and ST2-negative Foxp3+CD4+CD25+ T cells in ST2−/− mice that developed less hepatitis than BALB/c mice (p < 0.05), suggesting that ST2-negative Foxp3+CD4+CD25+ T cells reduced hepatitis. In patients, serum IL-33 and IPEX levels were correlated in controls (r2 = 0.5, p < 0.05), similar to the levels in mice, but not in anesthetic hepatitis patients (r2 = 0.01), who had elevated IL-33 (p < 0.001) and decreased IPEX (p < 0.01). Our results suggest that, in anesthetic, immune-mediated hepatitis, IL-33 does not regulate the CD4+ T-cell proliferation that initiates hepatitis, but IL-33, likely independent of ST2, reduces hepatitis via upregulation of Foxp3+CD4+CD25+ T cells. Further studies are needed to translate the role of IL-33 to human liver disease.

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References

  1. 1.

    Bell, L. N. & Chalasani, N. Epidemiology of idiosyncratic drug-induced liver injury. Semin Liver Dis. 29, 337–347 (2009).

  2. 2.

    Satoh, H. et al. Investigation of the immunological basis of halothane-induced hepatotoxicity. Adv. Exp. Med. Biol. 197, 657–673 (1986).

  3. 3.

    Bourdi, M. et al. Human cytochrome P450 2E1 is a major autoantigen associated with halothane hepatitis. Chem. Res. Toxicol. 9, 1159–1166 (1996).

  4. 4.

    Njoku, D. B. et al. A novel model of drug hapten-induced hepatitis with increased mast cells in the BALB/c mouse. Exp. Mol. Pathol. 78, 87–100 (2005).

  5. 5.

    Njoku, D. B. et al. Suppressive and pro-inflammatory roles for IL-4 in the pathogenesis of experimental drug-induced liver injury. Eur. J. Immunol. 39, 1652–1663 (2009).

  6. 6.

    Cho, J. et al. Sex bias in experimental immune-mediated, drug-induced liver injury in BALB/c mice: suggested roles for Tregs, estrogen, and IL-6. PLoS ONE 8, e61186 (2013).

  7. 7.

    Roth, G. A. et al. Up-regulation of interleukin 33 and soluble ST2 serum levels in liver failure. J. Surg. Res. 163, e79–e83 (2010).

  8. 8.

    Wang, J., Zhao, P., Guo, H., Sun, X., Jiang, Z., Xu, L. et al. Serum IL-33 levels are associated with liver damage in patients with chronic hepatitis C. Mediat. Inflamm. 2012, 819636 (2012).

  9. 9.

    Wang, J. et al. Serum IL-33 levels are associated with liver damage in patients with chronic hepatitis B. J. Interferon Cytokine Res. 32, 248–253 (2012).

  10. 10.

    Sakai, N. et al. Interleukin-33 is hepatoprotective during liver ischemia/reperfusion in mice. Hepatology 56, 1468–1478 (2012).

  11. 11.

    McHedlidze, T. et al. Interleukin-33-dependent innate lymphoid cells mediate hepatic fibrosis. Immunity 39, 357–371 (2013).

  12. 12.

    Li, J. et al. Biliary repair and carcinogenesis are mediated by IL-33-dependent cholangiocyte proliferation. J. Clin. Invest. 124, 3241–3251 (2014).

  13. 13.

    Milovanovic, M. et al. IL-33/ST2 axis in inflammation and immunopathology. Immunol. Res. 52, 89–99 (2012).

  14. 14.

    Arshad, M. I. et al. TRAIL but not FasL and TNFalpha, regulates IL-33 expression in murine hepatocytes during acute hepatitis. Hepatology 56, 2353–2362 (2012).

  15. 15.

    Volarevic, V. et al. Protective role of IL-33/ST2 axis in Con A-induced hepatitis. J. Hepatol. 56, 26–33 (2012).

  16. 16.

    Schiering, C. et al. The alarmin IL-33 promotes regulatory T-cell function in the intestine. Nature 513, 564–568 (2014).

  17. 17.

    Matta, B. M. et al. IL-33 is an unconventional Alarmin that stimulates IL-2 secretion by dendritic cells to selectively expand IL-33R/ST2+ regulatory T cells. J. Immunol. 193, 4010–4020 (2014).

  18. 18.

    Noel, G. et al. Ablation of interaction between IL-33 and ST2+ regulatory T cells increases immune cell-mediated hepatitis and activated NK cell liver infiltration. Am. J. Physiol. Gastrointest. Liver Physiol. 311, G313–G323 (2016).

  19. 19.

    Siede, J. et al. IL-33 receptor-expressing regulatory T cells are highly activated, Th2 biased and suppress CD4 T cell proliferation through IL-10 and TGFbeta release. PLoS ONE 11, e0161507 (2016).

  20. 20.

    Ryba-Stanislawowska, M., Werner, P., Skrzypkowska, M., Brandt, A. & Mysliwska, J. IL-33 effect on quantitative changes of CD4+CD25highFOXP3+ regulatory T cells in children with type 1 diabetes. Mediat. Inflamm. 2016, 9429760 (2016).

  21. 21.

    Kim, Y. H. et al. Anti-IL-33 antibody has a therapeutic effect in a murine model of allergic rhinitis. Allergy 67, 183–190 (2012).

  22. 22.

    Lee, H. Y. et al. Blockade of IL-33/ST2 ameliorates airway inflammation in a murine model of allergic asthma. Exp. Lung Res. 40, 66–76 (2014).

  23. 23.

    Njoku, D. B. et al. IP-10 protects while MIP-2 promotes experimental anesthetic hapten - induced hepatitis. J. Autoimmun. 32, 52–59 (2009).

  24. 24.

    Lopez, S. I. et al. Autoimmune hepatitis type 2 in a child with IPEX syndrome. J. Pediatr. Gastroenterol. Nutr. 53, 690–693 (2011).

  25. 25.

    Invernizzi, P. et al. Autoimmune hepatitis type 2 associated with an unexpected and transient presence of primary biliary cirrhosis-specific antimitochondrial antibodies: a case study and review of the literature. BMC Gastroenterol. 12, 92 (2012).

  26. 26.

    Kim, H. R. et al. Levels of circulating IL-33 and eosinophil cationic protein in patients with hypereosinophilia or pulmonary eosinophilia. J. Allergy Clin. Immunol. 126, 880–882 (2010).

  27. 27.

    Liang, Y., Jie, Z., Hou, L., Aguilar-Valenzuela, R., Vu, D., Soong, L. et al. IL-33 induces nuocytes and modulates liver injury in viral hepatitis. J. Immunol. 190, 5666–5675 (2013).

  28. 28.

    Oboki, K. et al. IL-33 is a crucial amplifier of innate rather than acquired immunity. Proc. Natl Acad. Sci. USA 107, 18581–18586 (2010).

  29. 29.

    Louten, J. et al. Endogenous IL-33 enhances Th2 cytokine production and T-cell responses during allergic airway inflammation. Int Immunol. 23, 307–315 (2011).

  30. 30.

    Rank, M. A. et al. IL-33-activated dendritic cells induce an atypical TH2-type response. J. Allergy Clin. Immunol. 123, 1047–1054 (2009).

  31. 31.

    Saraiva, M. & O’Garra, A. The regulation of IL-10 production by immune cells. Nat. Rev. Immunol. 10, 170–181 (2010).

  32. 32.

    Sattler, S. et al. IL-10-producing regulatory B cells induced by IL-33 (Breg(IL-33)) effectively attenuate mucosal inflammatory responses in the gut. J. Autoimmun. 50, 107–122 (2014).

  33. 33.

    Kurth, M. J., Yokoi, T. & Gershwin, M. E. Halothane-induced hepatitis: paradigm or paradox for drug-induced liver injury. Hepatology 60, 1473–1475 (2014).

  34. 34.

    Jaeschke, H., Xie, Y. & McGill, M. R. Acetaminophen-induced liver injury: from animal models to humans. J. Clin. Transl. Hepatol. 2, 153–161 (2014).

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Acknowledgements

The authors would like to acknowledge Dominic Thomas and Nicola Diny for their technical assistance and Nicole Muehleisen and Claire Levine for editorial assistance with this manuscript. This work was supported, in part, by the American Autoimmune Related Disease Association and Mr. and Mrs. Joseph Scoby and the Gail I Zuckerman foundations. Since, the initial submission of this manuscript, our technology transfer group informed us about a US patent involving the CYP2E1 epitope used in this publication. The information is as follows: Inventor: D.B.N., Invention Disclosure Title: Recognition of Critical CYP2E1 Epitopes, Issued Patent Title: Recognition of CYP2E1 Epitopes, US Patent application No. 13/203,402, Filed: 08/25/2014 by the Johns Hopkins University, Issued patent number: 9,339,531, Issue date: 5/17/2016.

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Affiliations

  1. Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, 1800 Orleans Street, Suite 6349, Baltimore, MD, 21287, USA

    • Merylin Cottagiri
    • , Maeva Nyandjo
    • , Matthew Stephens
    • , Joel J. Mantilla
    •  & Dolores B. Njoku
  2. RIKEN Center for Developmental Biology, 2-2-3 Minatojima Minamimachi, Chuo-ku, Kobe, Japan, 650-0047

    • Hirohisa Saito
  3. Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Melbourne, Australia

    • Ian R. Mackay
  4. Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis St., Boston, MA, 02115, USA

    • Noel R. Rose
  5. Department of Pathology, Johns Hopkins University, 720 Rutland Avenue, Baltimore, MD, 21205, USA

    • Dolores B. Njoku

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Conflict of interest

Ms. Cottagiri declares no potential conflict of interest. Ms Nyandjo declares no potential conflict of interest. Mr. Stephens declares no potential conflict of interest. Mr. Mantilla declares no potential conflict of interst. Dr. Saito declares no potential conlict of interest. Dr. Mackay delarees no potential conflict of interest. Dr. Rose declares no potential conflict of interest. Dr. Njoku owns a patent on the epitope utilized in this manuscript. There are no financial relationships or compensations associated with this patent.

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Correspondence to Dolores B. Njoku.

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https://doi.org/10.1038/s41423-018-0087-y