Didox (3,4-dihydroxybenzohydroxamic acid) suppresses IL-33-induced cytokine production in primary mouse mast cells

• Published in: Cellular immunology Vol. 319; pp. 10 - 16
• Main Authors: Caslin, Heather L., McLeod, Jamie Josephine Avila, Spence, Andrew J., Qayum, Amina Abdul, Kolawole, Elizabeth Motunrayo, Taruselli, Marcela T., Paranjape, Anuya, Elford, Howard L., Ryan, John J.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 01.09.2017
• Subjects: Acetylcysteine - pharmacology; Allergic inflammation; Animals; AP-1; Bone Marrow Cells - cytology; Bone Marrow Cells - drug effects; Bone Marrow Cells - immunology; Chemokine CCL3 - antagonists & inhibitors; Chemokine CCL3 - genetics; Chemokine CCL3 - immunology; Didox; Female; Gene Expression Regulation - drug effects; Gene Expression Regulation - immunology; Genes, Reporter; Hydroxamic Acids - pharmacology; Hydroxyurea - pharmacology; IL-33; Immunosuppressive Agents - pharmacology; Interleukin-13 - antagonists & inhibitors; Interleukin-13 - genetics; Interleukin-13 - immunology; Interleukin-33 - antagonists & inhibitors; Interleukin-33 - pharmacology; Lipopolysaccharides - pharmacology; Luciferases - genetics; Luciferases - immunology; Male; Mast cells; Mast Cells - cytology; Mast Cells - drug effects; Mast Cells - immunology; Mice; Mice, Inbred C57BL; NF-kappa B - antagonists & inhibitors; NF-kappa B - genetics; NF-kappa B - immunology; NFκB; Primary Cell Culture; Signal Transduction; Transcription Factor AP-1 - antagonists & inhibitors; Transcription Factor AP-1 - genetics; Transcription Factor AP-1 - immunology; Tumor Necrosis Factor-alpha - antagonists & inhibitors; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - immunology; NAC; Allergic inflammation; NFκB; RNR; Didox; Mast cells; HU; IL-33; AP-1; BMMC; LPS
• ISSN: 0008-8749; 1090-2163
• DOI: 10.1016/j.cellimm.2017.04.013

•Didox suppresses IL-33-induced mast cell cytokine production.•Didox-mediated suppression is 100-fold more potent than N-acetylcysteine effects.•Didox attenuates NFκB and AP-1 transcriptional activities. While IgE is considered the primary mediator of mast cell activation, IL-33 contributes substantially in asthma, allergic rhinitis, and atopic dermatitis. To develop effective treatments for allergic disease, it is important to understand the role of therapeutic agents on IL-33 activation. We examined the effect of Didox (3,4-dihydroxybenzohydroxamic acid), an antioxidant and ribonucleotide reductase (RNR) inhibitor, on IL-33-mediated mast cell activation. Didox suppressed IL-6, IL-13, TNF, and MIP-1α (CCL3) production in bone marrow derived mast cells following IL-33 activation. This suppression was observed in different genetic backgrounds and extended to peritoneal mast cells. The antioxidant N-acetylcysteine mimicked the suppression of Didox, albeit at a much higher dose, while the RNR inhibitor hydroxyurea had no effect. Didox substantially suppressed IL-33-mediated NFκB and AP-1 transcriptional activities. These results suggest that Didox attenuates IL-33-induced mast cell activation and should be further studied as a potential therapeutic agent for inflammatory diseases involving IL-33.