Inosine pranobex enhances human NK cell cytotoxicity by inducing metabolic activation and NKG2D ligand expression

Michael T. McCarthy, Da Lin, Tomoyoshi Soga, Julie Adam, Christopher A. O'Callaghan

Research output: Contribution to journalArticle

Abstract

Inosine pranobex (IP) is a synthetic immunomodulating compound, indicated for use in the treatment of human papillomavirus-associated warts and subacute sclerosing panencephalitis. Previous studies demonstrate that the immunomodulatory activity of IP is characterized by enhanced lymphocyte proliferation, cytokine production, and NK cell cytotoxicity. The activation of NKG2D signaling on NK cells, CD8+ T cells, and γδ T cells also produces these outcomes. We hypothesized that IP alters cellular immunity through the induction of NKG2D ligand expression on target cells, thereby enhancing immune cell activation through the NKG2D receptor. We tested this hypothesis and show that exposure of target cells to IP leads to increased expression of multiple NKG2D ligands. Using both targeted metabolic interventions and unbiased metabolomic studies, we found that IP causes an increase in intracellular concentration of purine nucleotides and tricarboxylic acid (TCA) cycle intermediates and NKG2D ligand induction. The degree of NKG2D ligand induction was functionally significant, leading to increased NKG2D-dependent target cell immunogenicity. These findings demonstrate that the immunomodulatory properties of IP are due to metabolic activation with NKG2D ligand induction.

Original languageEnglish
JournalEuropean Journal of Immunology
DOIs
Publication statusAccepted/In press - 2019 Jan 1

Fingerprint

Inosine Pranobex
Natural Killer Cells
Ligands
NK Cell Lectin-Like Receptor Subfamily K
Subacute Sclerosing Panencephalitis
Purine Nucleotides
T-Lymphocytes
Warts
Metabolomics
Citric Acid Cycle
Cellular Immunity
Metabolic Activation
Lymphocytes
Cytokines

Keywords

  • immunomodulation
  • innate immunity
  • inosine pranobex
  • MICA
  • NKG2D

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Inosine pranobex enhances human NK cell cytotoxicity by inducing metabolic activation and NKG2D ligand expression. / McCarthy, Michael T.; Lin, Da; Soga, Tomoyoshi; Adam, Julie; O'Callaghan, Christopher A.

In: European Journal of Immunology, 01.01.2019.

Research output: Contribution to journalArticle

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