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Didox (3,4-dihydroxybenzohydroxamic acid) suppresses IgE-mediated mast cell activation through attenuation of NFκB and AP-1 transcription.
Didox (3,4-dihydroxybenzohydroxamic acid) suppresses IgE-mediated mast cell activation through attenuation of NFκB and AP-1 transcription.
- Source :
-
Cellular immunology [Cell Immunol] 2017 Dec; Vol. 322, pp. 41-48. Date of Electronic Publication: 2017 Sep 21. - Publication Year :
- 2017
-
Abstract
- Mast cell activation via the high-affinity IgE receptor (FcεRI) elicits production of inflammatory mediators central to allergic disease. As a synthetic antioxidant and a potent ribonucleotide reductase (RNR) inhibitor, Didox (3,4-dihyroxybenzohydroxamic acid) has been tested in clinical trials for cancer and is an attractive therapeutic for inflammatory disease. We found that Didox treatment of mouse bone marrow-derived mast cells (BMMC) reduced IgE-stimulated degranulation and cytokine production, including IL-6, IL-13, TNF and MIP-1a (CCL3). These effects were consistent using BMMC of different genetic backgrounds and peritoneal mast cells. While the RNR inhibitor hydroxyurea had little or no effect on IgE-mediated function, high concentrations of the antioxidant N-acetylcysteine mimicked Didox-mediated suppression. Furthermore, Didox increased expression of the antioxidant genes superoxide dismutase and catalase, and suppressed DCFH-DA fluorescence, indicating reduced reactive oxygen species production. Didox effects were not due to changes in FcεRI expression or cell viability, suggesting it inhibits signaling required for inflammatory cytokine production. In support of this, we found that Didox reduced FcεRI-mediated AP-1 and NFκB transcriptional activity. Finally, Didox suppressed mast cell-dependent, IgE-mediated passive systemic anaphylaxis in vivo. These data demonstrate the potential use for Didox asa means of antagonizing mast cell responses in allergic disease.<br /> (Copyright © 2017 Elsevier Inc. All rights reserved.)
- Subjects :
- Acetylcysteine pharmacology
Animals
Bone Marrow Cells immunology
Catalase biosynthesis
Cell Degranulation drug effects
Cells, Cultured
Chemokine CCL3 biosynthesis
Hypersensitivity immunology
Interleukin-13 biosynthesis
Interleukin-6 biosynthesis
Mast Cells drug effects
Mice
Mice, Inbred C57BL
Oxidative Stress drug effects
Oxidative Stress immunology
Reactive Oxygen Species metabolism
Superoxide Dismutase biosynthesis
Transcription, Genetic drug effects
Tumor Necrosis Factor-alpha biosynthesis
Anti-Inflammatory Agents pharmacology
Antioxidants pharmacology
Hydroxamic Acids pharmacology
Hypersensitivity drug therapy
Immunoglobulin E immunology
Mast Cells immunology
NF-kappa B genetics
Transcription Factor AP-1 genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1090-2163
- Volume :
- 322
- Database :
- MEDLINE
- Journal :
- Cellular immunology
- Publication Type :
- Academic Journal
- Accession number :
- 28964543
- Full Text :
- https://doi.org/10.1016/j.cellimm.2017.09.008