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Inosine pranobex enhances human NK cell cytotoxicity by inducing metabolic activation and NKG2D ligand expression
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 prolifera...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6972573/ https://www.ncbi.nlm.nih.gov/pubmed/31434164 http://dx.doi.org/10.1002/eji.201847948 |
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author | McCarthy, Michael T. Lin, Da Soga, Tomoyoshi Adam, Julie O'Callaghan, Christopher A. |
author_facet | McCarthy, Michael T. Lin, Da Soga, Tomoyoshi Adam, Julie O'Callaghan, Christopher A. |
author_sort | McCarthy, Michael T. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-6972573 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-69725732020-01-27 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. Eur J Immunol Immunomodulation and immune therapies 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. John Wiley and Sons Inc. 2019-09-12 2020-01 /pmc/articles/PMC6972573/ /pubmed/31434164 http://dx.doi.org/10.1002/eji.201847948 Text en © 2019 The Authors. European Journal of Immunology published by WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Immunomodulation and immune therapies McCarthy, Michael T. Lin, Da Soga, Tomoyoshi Adam, Julie O'Callaghan, Christopher A. Inosine pranobex enhances human NK cell cytotoxicity by inducing metabolic activation and NKG2D ligand expression |
title | Inosine pranobex enhances human NK cell cytotoxicity by inducing metabolic activation and NKG2D ligand expression |
title_full | Inosine pranobex enhances human NK cell cytotoxicity by inducing metabolic activation and NKG2D ligand expression |
title_fullStr | Inosine pranobex enhances human NK cell cytotoxicity by inducing metabolic activation and NKG2D ligand expression |
title_full_unstemmed | Inosine pranobex enhances human NK cell cytotoxicity by inducing metabolic activation and NKG2D ligand expression |
title_short | Inosine pranobex enhances human NK cell cytotoxicity by inducing metabolic activation and NKG2D ligand expression |
title_sort | inosine pranobex enhances human nk cell cytotoxicity by inducing metabolic activation and nkg2d ligand expression |
topic | Immunomodulation and immune therapies |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6972573/ https://www.ncbi.nlm.nih.gov/pubmed/31434164 http://dx.doi.org/10.1002/eji.201847948 |
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