1‐Fluoro‐2,4‐dinitrobenzene and its derivatives act as secretagogues on rodent mast cells

Abstract

Accumulating evidence suggests that activated mast cells are involved in contact hypersensitivity, although the precise mechanisms of their activation are still not completely understood. We investigated the potential of common experimental allergens to induce mast cell activation using murine bone marrow-derived cultured mast cells and rat peritoneal mast cells. Among these allergens, 1-chloro-2,4-dinitrobenzene and 1-fluoro-2,4-dinirobenzene (DNFB) were found to induce degranulation of rat peritoneal mast cells. DNFB-induced degranulation is accompanied by cytosolic Ca 2+ mobilization and is significantly inhibited by pertussis toxin, U73122 (a phospholipase C inhibitor), and BAPTA (a Ca 2+ chelator), raising the possibility that DNFB acts on the G protein-coupled receptors and activates G i , which induces activation of phospholipase C, as well as known mast cell secretagogues, such as compound 48/80. DNFB could induce mast cell degranulation in the absence of serum proteins and IgE. Structure-activity relationship analyses revealed an inverse correlation between the degree of degranulation and the electron density of the C1 carbon of the DNFB derivatives. These findings raise a possibility that DNFB functions as a potent contact allergen through induction of cutaneous mast cell degranulation.Keywords: Contact hypersensitivity r 1-Fluoro-2,4-dinitrobenzene r Histamine r Inflammation r Mast cells Additional supporting information may be found in the online version of this article at the publisher's web-site Correspondence: Prof. Satoshi Tanaka e-mail: tanaka-s@okayama-u.ac.jp IntroductionA series of recent studies have enriched our understanding about the pathology of contact hypersensitivity [1]. Contact hypersensitivity was initially recognized as an allergic responses induced C 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2017. 47: 60-67 Innate immunity 61 mainly by activated T cells but now is regarded as the complex process involving many kinds of immune cells in addition to T cells. Chemical compounds, such as 1-fluoro-2,4-dinitrobenzene (DNFB), oxazolone, and picryl chloride, have been used for induction of contact hypersensitivity [2]. These models have revealed that self-proteins conjugated with these compounds induced Tcell-mediated immune responses, which required dendritic cell migration. Although it has long been controversial whether mast cells are involved in contact hypersensitivity, a series of the transfer experiments has indicated that IgE and mast cells could initiate immune responses in several models [3,4]. Recent studies have expanded the pathological roles of IgE and cutaneous mast cells in murine contact hypersensitivity models [5,6]. Bryce et al. demonstrated that successful contact hypersensitivity with oxazolone should require mast cells equipped with IgE [7]. Cutaneous mast cells were found to promote dendritic cell migration into the draining lymph node, which is regarded as the primary step of contact hypersensitivity, through the release...

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“…Indeed, Dudeck et al reported MC degranulation in skin sections obtained 4 h after sensitization with DNFB ( 59 ). A recent report also shows that DNFB, but not oxazolone, can induce direct degranulation of rat PMCs in vitro ( 74 ). MC activation has been best visualized in the effector phase using two-photon microscopy.…”

MRGPRX2-Mediated Degranulation of Human Skin Mast Cells Requires the Operation of Gαi, Gαq, Ca++ Channels, ERK1/2 and PI3K—Interconnection between Early and Late Signaling

“…The following supporting information can be downloaded at: https: //www.mdpi.com/article/10.3390/cells11060953/s1, Figure S1: The inhibitors employed in main Figure 1 exert no cytotoxicity on cultured skin MC; Figure S2: MC degranulation via MRGPRX2 relies on Gαi, Gαq and calcium mobilization as evidenced by histamine release; Figure S3: The survival of ex vivo skin MC is not perceptibly compromised by the inhibitors employed in main Figure 1; Figure S4: Differences between c48/80 and SP from main Figure 1; Figure S5: Comparison between cultured and ex vivo skin MCs from main Figure 1; Figure S6: The inhibitors employed in main Figure 2 exert no cytotoxicity on cultured skin MC; Figure S7: The survival of ex vivo skin MCs is not perceptibly compromised by the inhibitors employed in main Figure 2; Figure S8: Differences between c48/80 and SP from main Figure 2; S1: Inhibitors employed and their primary targets. References [15,30,31,33,36,38,39,44,49,51,55,[60][61][62][86][87][88][89][90][91][92][93][94][95][96] are cited in the Supplementary materials.…”

Persistent Extracellular Signal-Regulated Kinase Activation by the Histamine H4 Receptor in Spinal Neurons Underlies Chronic Itch

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