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

Cell Mol Immunol. 2019 Aug;16(8):706-717. doi: 10.1038/s41423-018-0087-y. Epub 2018 Jul 20.

Abstract

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.

Keywords: Foxp3+ Tregs; IL-33; autoimmunity; drug-induced; hepatitis; immune-mediated.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes / metabolism*
  • Cell Proliferation / genetics
  • Chemical and Drug Induced Liver Injury / blood*
  • Chemical and Drug Induced Liver Injury / immunology*
  • Chemical and Drug Induced Liver Injury / mortality
  • Cytochrome P-450 CYP2E1 / immunology
  • Disease Models, Animal
  • Epitopes / chemistry
  • Epitopes / pharmacology
  • Female
  • Fluoroacetates / chemistry
  • Fluoroacetates / pharmacology
  • Forkhead Transcription Factors / blood*
  • Forkhead Transcription Factors / metabolism*
  • Humans
  • Interleukin-1 Receptor-Like 1 Protein / genetics
  • Interleukin-1 Receptor-Like 1 Protein / metabolism
  • Interleukin-2 Receptor alpha Subunit / metabolism
  • Interleukin-33 / blood*
  • Interleukin-33 / genetics
  • Interleukin-33 / metabolism*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout

Substances

  • Epitopes
  • FOXP3 protein, human
  • Fluoroacetates
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • IL2RA protein, human
  • IL33 protein, human
  • Il1rl1 protein, mouse
  • Il33 protein, mouse
  • Interleukin-1 Receptor-Like 1 Protein
  • Interleukin-2 Receptor alpha Subunit
  • Interleukin-33
  • trifluoroacetyl chloride
  • Cytochrome P-450 CYP2E1
  • cytochrome P-450 2E1, mouse