Eltrombopag inhibits Type I interferon-mediated antiviral signaling by decreasing cellular iron

Biochem Pharmacol. 2021 Apr:186:114436. doi: 10.1016/j.bcp.2021.114436. Epub 2021 Feb 1.

Abstract

Thrombocytopenia is common among patients with viral hepatitis, limiting the use of antiviral therapy. Eltrombopag (EP) is a thrombopoietin receptor (TPO-R) agonist that has been approved for treatment of immune thrombocytopenia patients with hepatitis virus infection. Interferon-α (IFN-α) plays a crucial role in the antiviral response, and is recommended as the first-line agent for chronic hepatitis B patients. Here, we investigated whether EP inhibits the production of IFN-stimulated genes (ISGs) induced by IFN-α through the TPO-R-independent pathway by mediating reactive oxygen species production by iron chelation. Our results assessed the inhibitory effect of EP on IFN-α signaling, which contributes to the downregulation of ISGs produced by monocytes and sheds light on the underlying mechanisms using iron chelation to treat patients with hepatitis-related immunological thrombocytopenia.

Keywords: Eltrombopag; IFN-stimulated gene; Interferon-α; Iron chelation; Reactive oxygen species; Thrombocytopenia; Viral hepatitis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Antiviral Agents / antagonists & inhibitors
  • Antiviral Agents / metabolism*
  • Benzoates / pharmacology*
  • Benzoates / therapeutic use
  • Cell Survival / drug effects
  • Cell Survival / physiology
  • Cells, Cultured
  • Female
  • Hepatitis B, Chronic / drug therapy
  • Hepatitis B, Chronic / metabolism
  • Humans
  • Hydrazines / pharmacology*
  • Hydrazines / therapeutic use
  • Interferon-alpha / antagonists & inhibitors
  • Interferon-alpha / metabolism*
  • Iron / metabolism*
  • Leukocytes, Mononuclear / drug effects
  • Leukocytes, Mononuclear / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Middle Aged
  • Pyrazoles / pharmacology*
  • Pyrazoles / therapeutic use
  • Receptors, Thrombopoietin / agonists
  • Receptors, Thrombopoietin / metabolism
  • THP-1 Cells / drug effects
  • THP-1 Cells / metabolism
  • Thrombocytopenia / drug therapy
  • Thrombocytopenia / metabolism

Substances

  • Antiviral Agents
  • Benzoates
  • Hydrazines
  • Interferon-alpha
  • Pyrazoles
  • Receptors, Thrombopoietin
  • Iron
  • eltrombopag