Didox (3,4-dihydroxybenzohydroxamic acid) suppresses IgE-mediated mast cell activation through attenuation of NFκB and AP-1 transcription

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 as a means of antagonizing mast cell responses in allergic disease.

Lobeglitazone Attenuates Airway Inflammation and Mucus Hypersecretion in a Murine Model of Ovalbumin-Induced Asthma

“…According to previous studies, AP-1 expression was elevated in RAW264.7 cells by lipopolysaccharide treatment and induced the production of proinflammatory cytokines ( Han et al, 2017 ; Ahn et al, 2018 ). Because of this evidence, NF-κB and AP-1 are considered potential therapeutic targets in various inflammatory diseases ( Lee et al, 2017 ; McLeod et al, 2017 ). Furthermore, the expression of NF-κB and AP-1 leads to the production of MUC5AC that are major gel-forming mucins in airway secretions ( Lee et al, 2017 ; Ding et al, 2018 ).…”

“…Of these factors, increased T helper (Th)2 cytokines are believed to be a crucial pathophysiological cause of asthma, because they are closely associated with eosinophil recruitment, maturation and activation ( Lee et al, 2010 ). In addition, the transcription factors activator protein (AP)-1 and nuclear factor-kappa B (NF-κB) are involved in the progression of inflammatory responses ( McLeod et al, 2017 ). They are activated by various harmful stimuli, after which they translocate into the nucleus and bind to their promoter lesions.…”

FcεRI-HDAC3-MCP1 Signaling Axis Promotes Passive Anaphylaxis Mediated by Cellular Interactions

“…Omalizumab, an anti-IgE antibody, can prevent anaphylaxis in patients with mastocytosis [23,24] and exercise-induced anaphylaxis [25]. Mast cells express the high-affinity IgE receptor FcεRI and mediate IgE-dependent allergies and anaphylaxis, such as PCA and food-induced systemic anaphylaxis [2,6,26,27,28,29,30]. IgE can bind to FcεRI on the surfaces of blood basophils, tissue-resident mast cells and other cell types, including neutrophils, eosinophils, both monocytes and dendritic cells and platelets (Figure 1).…”