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  • br STAR Methods br Author Contributions br Acknowledgments

    2022-11-18


    STAR★Methods
    Author Contributions
    Acknowledgments We thank Craig D. Wenger and Neva C. Durand for helpful advice, guidance, and discussions. D.H.P. is supported by the NIH National Human Genome Research Institute (NHGRI) (grant R00HG008662) and the Damon Runyon Cancer Research Foundation (DRG-2122-12). K.V.B. is supported by the NIH National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (grant F32DK107112). G.T.H. is supported by the NIH (grant T32HG000044). M.I.L. is supported by the NIH National Cancer Institute (NCI) (grant CA142538-07). D.S. was supported by an NIH T32 fellowship (HG000044) and a Genentech Graduate Fellowship. This research was supported by the NIH Centers of Excellence in Genomic Science (CEGS) (grant 5P50HG00773502). E.L.A. is supported by an NIH New Innovator Award (1DP2OD008540), an NSF Physics Frontiers Center Award (PHY-1427654, Center for Theoretical Biological Physics), the NHGRI Center for Excellence for Genomic Sciences (HG006193), the Welch Foundation (Q-1866), an NVIDIA Research Center Award, an IBM University Challenge Award, a Google Research Award, a Cancer Prevention Research Institute of Texas Scholar Award (R1304), a McNair Medical Institute Scholar Award, the NIH (4D Nucleome grant U01HL130010 and NIH Encyclopedia of DNA Elements Mapping Center Award UM1HG009375), and the President’s Early Career Award in Science and Engineering. Illumina sequencing services were performed by the Stanford Center for Genomics and Personalized Medicine. The content is solely the responsibility of the authors and does not represent the official views of the NIH. M.P.S. is a founder and member of the science advisory board of Personalis and Qbio and a science advisory board member of Genapsys and Epinomics.
    Introduction Mast gsk525762 are most recognized for their role in allergic disease. Antigen-induced cross-linkage of surface-bound IgE activates the high-affinity IgE receptor, FcεRI, and leads to the two distinct phases of mast cell activation [1], [2], [3], [4], [5], [6]. The first phase, degranulation, occurs immediately and is noted by release of preformed inflammatory mediators such as histamine and proteases. The second phase occurs several hours later, and is marked by de novo production and secretion of arachidonic acid metabolites and many cytokines, including IL-4, IL-6, IL-13, MIP-1a, MCP-1, TNF, GM-CSF and VEGF. While these mediators are necessary for inflammation associated with acute allergic responses, recent evidence suggests that chronic mast cell activation also contributes to harmful inflammatory diseases such as rheumatoid arthritis, multiple sclerosis and heart disease [7], [8], [9], [10]. As such, mast cells have become an important target for therapeutic intervention in these maladies. The synthetic antioxidant and potent ribonucleotide reductase (RNR) inhibitor Didox (3,4-dihyroxybenzohydroxamic acid) has become an attractive therapeutic for treatment of inflammatory diseases [11], [12], [13]. Originally developed as an antineoplastic and antiproliferative agent to improve upon the activities of hydroxyurea, Didox possesses both iron chelating and free-radical scavenging function. Didox exhibits greater RNR inhibition than hydroxyurea, with minimal in vivo toxicity [11], [14], [15], [16]. In addition to its anti-neoplastic activity, more recent studies have shown suppressive effects on immune cell activation. Inayat and colleagues found that Didox suppresses T cell proliferation and cytokine production following anti-CD3 activation that models organ rejection or graft-versus-host disease [17]. Didox treatment of LPS-stimulated RAW264.7 macrophage cells in vitro reduced the expression of inflammatory genes without causing cytotoxicity [18]. Furthermore, we recently published that Didox suppresses IL-33-mediated mast cell activation in vitro[19]. These observations prompted us to study Didox effects on IgE-mediated mast cell activation. Here we report that Didox antagonizes IgE-induced degranulation, cytokine production, transcription factor function, and passive systemic anaphylaxis. These data support further study of this drug’s potential for understanding and treating allergic disease.