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

Cell Immunol. 2017 Sep:319:10-16. doi: 10.1016/j.cellimm.2017.04.013. Epub 2017 Jul 11.

Abstract

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.

Keywords: AP-1; Allergic inflammation; Didox; IL-33; Mast cells; NFκB.

MeSH terms

  • Acetylcysteine / pharmacology
  • Animals
  • Bone Marrow Cells / cytology
  • Bone Marrow Cells / drug effects
  • Bone Marrow Cells / immunology
  • Chemokine CCL3 / antagonists & inhibitors
  • Chemokine CCL3 / genetics
  • Chemokine CCL3 / immunology
  • Female
  • Gene Expression Regulation / drug effects*
  • Gene Expression Regulation / immunology
  • Genes, Reporter
  • Hydroxamic Acids / pharmacology*
  • Hydroxyurea / pharmacology
  • 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 / 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
  • 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

Substances

  • Ccl3 protein, mouse
  • Chemokine CCL3
  • Hydroxamic Acids
  • Il33 protein, mouse
  • Immunosuppressive Agents
  • Interleukin-13
  • Interleukin-33
  • Lipopolysaccharides
  • NF-kappa B
  • Transcription Factor AP-1
  • Tumor Necrosis Factor-alpha
  • Luciferases
  • 3,4-dihydroxybenzohydroxamic acid
  • Acetylcysteine
  • Hydroxyurea