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

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

doi:10.1016/j.cellimm.2017.04.013

Cited by 6 publications

(6 citation statements)

References 40 publications

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“…These results corroborate previous research, where Didox treatment antagonized pro-inflammatory responses of anti-CD3-activated T cells and LPS-stimulated macrophages in allotransplant and macrophage inflammatory disease models, respectfully [17,18]. Additionally, these data agree with Didox effects on IL-33-mediated mast cell activation [19]. Collectively, these results indicate Didox may have broad anti-inflammatory effects.…”

Section: Discussionsupporting

confidence: 91%

“…In addition to antiproliferative effects, Didox possesses antioxidant and anti-inflammatory activity with significant therapeutic potential to treat diseases associated with oxidative stress and inflammation [17,18,38]. We have recently published Didox suppression of IL-33 mediated mast cell activation [19], however IgE-mediated mast cell function has not been studied. Here we investigated Didox effects in vitro and in vivo and the implications they may have for treating allergic inflammation.…”

Section: Discussionmentioning

confidence: 99%

“…Most experiments were conducted using mouse bone marrow-derived mast cells (BMMC), which were derived by culture for at least 21 days in complete RPMI supplemented as previously described, with ≥90% FceRI + and cKit + mast cells present by day 21 [19–21]. Cultures were used for up to 8 weeks of age and age-matched in experiments.…”

Section: Methodsmentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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

McLeod

Caslin

Spence

et al. 2017

Cellular Immunology

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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.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

McLeod

Caslin

Spence

et al. 2017

Cellular Immunology

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“…In recent years, a number of studies have identified compounds that inhibit IL-33 mediated activation of MCs. Amongst those are natural compounds from plants like berberine ( 111 ), methoxyluteolin ( 112 ), and resveratrol ( 113 ) or ES-62 produced from parasitic worms ( 114 ) as well as various other drug classes including didox (synthetic ribonucleotide reductase inhibitor) ( 115 ), chondroitin sulfate (glycosaminoglycan) ( 116 ), triochastatin A (histone deacetylase inhibitor) ( 117 ) and the growth factor TGFb1 ( 118 ). However, in all these studies, drug effects were investigated exclusively in vitro .…”

Section: Therapeutic Targeting Of the Il33-mc Axismentioning

confidence: 99%

IL33 and Mast Cells—The Key Regulators of Immune Responses in Gastrointestinal Cancers?

2020

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The Interleukin (IL-)1 family IL33 is best known for eliciting type 2 immune responses by stimulating mast cells (MCs), regulatory T-cells (Tregs), innate lymphoid cells (ILCs) and other immune cells. MCs and IL33 provide critical control of immunological and epithelial homeostasis in the gastrointestinal (GI) tract. Meanwhile, the role of MCs in solid malignancies appears tissue-specific with both pro and anti-tumorigenic activities. Likewise, IL33 signaling significantly shapes immune responses in the tumor microenvironment, but these effects remain often dichotomous when assessed in experimental models of cancer. Thus, the balance between tumor suppressing and tumor promoting activities of IL33 are highly context dependent, and most likely dictated by the mixture of cell types responding to IL33. Adding to this complexity is the promiscuous nature by which MCs respond to cytokines other than IL33 and release chemotactic factors that recruit immune cells into the tumor microenvironment. In this review, we integrate the outcomes of recent studies on the role of MCs and IL33 in cancer with our own observations in the GI tract. We propose a working model where the most abundant IL33 responsive immune cell type is likely to dictate an overall tumor-supporting or tumor suppressing outcome in vivo. We discuss how these opposing responses affect the therapeutic potential of targeting MC and IL33, and highlight the caveats and challenges facing our ability to effectively harness MCs and IL33 biology for anti-cancer immunotherapy.

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Involvement of the Negative Feedback of IL-33 Signaling in the Anti-Inflammatory Effect of Electro-acupuncture on Allergic Contact Dermatitis via Targeting MicroRNA-155 in Mast Cells

Wang

Long

et al. 2018

Inflammation

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In this study, we aimed to investigate the effect of electro-acupuncture (EA) at the Zusanli acupoint (ST36) on interleukin (IL)-33-mediated mast cell activation. Firstly, 2,4-dinitrofluorobenzene (DNFB)-induced allergic contact dermatitis (ACD) in rats was developed with or without EA treatment. Then, rat peritoneal mast cells (RPMCs) were obtained and cultured in the presence of IL-33. EA treatment relieved ear swelling and reduced mast cell infiltration in the local inflammation area with DNFB challenge, accompanying the decrement of IL-33 production. RPMCs isolated from ACD rats with EA treatment showed significant downregulation of IL-6, TNF-α, IL-13, and MCP-1 production following IL-33 stimulation. However, there was no obvious difference in surface ST2 receptor expression among different groups. In addition, EA selectively altered IL-33 signaling, suppressing p38 phosphorylation as well as NF-κB- and AP-1-mediated transcription but not Akt phosphorylation. Importantly, EA lowered microRNA (miR)-155 expression in the RPMCs, which presented a positive correlation with IL-33-induced IL-6 production. Furthermore, overexpression of miR-155 in the RPMCs was established following miR-155 mimic transfection. RPMCs with the overexpressed miR-155 displayed an obvious increment of inflammatory cytokine and abrogated the inhibitive effect of EA on NF-κB- and AP-1-regulated transcription in response to IL-33 compared with those without transfected-miR-155. These findings demonstrate EA treatment inhibits NF-κB and AP-1 activation as well as promotes the negative feedback regulation of IL-33 signaling via targeting miR-155 in mast cells, which contribute to the anti-inflammatory effect of EA on DNFB-induced ACD in rats.

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

Cited by 6 publications

References 40 publications

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

IL33 and Mast Cells—The Key Regulators of Immune Responses in Gastrointestinal Cancers?

Involvement of the Negative Feedback of IL-33 Signaling in the Anti-Inflammatory Effect of Electro-acupuncture on Allergic Contact Dermatitis via Targeting MicroRNA-155 in Mast Cells

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