Suppression of IgE-Independent Degranulation of Murine Connective Tissue-Type Mast Cells by Dexamethasone

Yamada, Keiko; Sato, Hitomi; Sakamaki, Kazuma; Kamada, Mayumi; Okuno, Yasushi; Fukuishi, Nobuyuki; Furuta, Kazuyuki; Tanaka, Satoshi

doi:10.20944/preprints201901.0003.v1

Cited by 9 publications

(4 citation statements)

References 24 publications

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“…Both methods induced mast cell degranulation, as shown by the release of histamine and β‐hexosaminidase. The inhibition of both signs of degranulation by tozasertib was similar to the anti‐allergic effects of dexamethasone (Yamada et al, 2019).…”

Section: Discussionsupporting

confidence: 58%

“…We assessed mast cell activation by quantitating histamine and β‐hexosaminidase release from IgE/antigen (Ag)‐stimulated rat basophilic leukaemia cells (RBLs) and bone marrow‐derived mast cells (BMMCs) and in phorbol‐12‐myristate 13‐acetate plus calcium ionophore (PMACI)‐stimulated human LAD2 mast cells (Gao et al, 2017). These stimuli were used to induce cell degranulation in activated mast cells as an in vitro model of activated mast cells (Yamada et al, 2019). We used the passive cutaneous anaphylaxis (PCA) mouse model with IgE/Ag induction and the ovalbumin (OVA)‐induced active systemic anaphylaxis (ASA) mouse model to evaluate the inhibitory effects of tozasertib on IgE‐mediated allergic reactions (Castillo‐Courtade et al, 2015; Kee & Hong, 2017).…”

Section: Introductionmentioning

confidence: 99%

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Aurora kinase inhibitor tozasertib suppresses mast cell activation in vitro and in vivo

Zhang

Sun

et al. 2020

British J Pharmacology

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Background and Purpose: Mast cells are important in allergic reactions. Here, we assessed the anti-allergic effects of the anti-cancer drug tozasertib specifically regarding regulatory effects on mast cell activation. Experimental Approach: Tozasertib effects on mast cell degranulation were determined by measuring β-hexosaminidase and histamine release and by assessing morphological changes in RBL-2H3 and mouse bone marrow-derived mast cells (BMMCs) stimulated with mouse anti-dinitrophenyl (DNP)-IgE/DNP-human serum albumin or human LAD2 cells activated with phorbol-12-myristate 13-acetate plus calcium ionophore (PMACI). Western blots were performed to detect the expression of molecules involved in NF-κB, MAPK, and Aurora kinase signalling. in vivo antiallergic effects of tozasertib were determined in the murine IgE-mediated passive cutaneous anaphylaxis (PCA) and ovalbumin (OVA)-induced active systemic anaphylaxis (ASA) models. Key Results: Tozasertib treatment decreased high-affinity IgE receptor (FcεRI) or PMACI-mediated degranulation in RBL-2H3 cells and in BMMCs or LAD2 cells as shown by β-hexosaminidase or histamine levels. Similarly, tozasertib prevented morphological changes in mast cells, such as particle release and F-actin reorganization. In addition, tozasertib markedly decreased expression of phosphorylated (p)-NF-κB p65, p-Erk1/2, p-p38, and p-Aurora A/B, indicating that tozasertib can inhibit the signalling pathway mediating mast cell activation. Tozasertib attenuated IgE/Ag-induced PCA dose-dependently, as shown by reduced Evans blue staining. Similarly, tozasertib reduced body temperature levels and serum histamine levels in OVAchallenged ASA mice. Conclusion and Implications:The Aurora kinase inhibitor tozasertib suppressed mast cell activation in vitro and in vivo. Tozasertib may be a potential drug, targeting mast cell activation, to treat allergic diseases or mastocytosis.

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Section: Discussionsupporting

confidence: 58%

Section: Introductionmentioning

confidence: 99%

Aurora kinase inhibitor tozasertib suppresses mast cell activation in vitro and in vivo

Zhang

Sun

et al. 2020

British J Pharmacology

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“…To go further, we investigated monocyte recruitment in ears because MCs expressing MRGPRX2 are prevalent in ear tissues. 66,67 Intradermal injection of P17 in ear increased the inflammation because it causes local and controlled allergic reaction. Hematoxylin and eosin stain on the ear tissues showed significant increase in ear thickness on the P17-injected ears as compared with the saline control.…”

Section: Effect Of P17 In Paw Edema and Vascular Permeability Through Evans Blue Extravasation Assay And Monocyte Recruitment In Mice Earmentioning

confidence: 99%

P17 induces chemotaxis and differentiation of monocytes via MRGPRX2-mediated mast cell–line activation

Duraisamy

Singh

Kumar

et al. 2022

Journal of Allergy and Clinical Immunology

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Background: P17, a peptide isolated from Tetramorium bicarinatum ant venom, is known to induce an alternative phenotype of human monocyte-derived macrophages via activation of an unknown G protein-coupled receptor (GPCR). Objective: We sought to investigate the mechanism of action and the immunomodulatory effects of P17 mediated through MRGPRX2 (Mas-related G protein-coupled receptor X2). Methods: To identify the GPCR for P17, we screened 314 GPCRs. Upon identification of MRGPRX2, a battery of in silico, in vitro, ex vivo, and in vivo assays along with the receptor mutation studies were performed. In particular, to investigate the immunomodulatory actions, we used b-hexosaminidase release assay, cytokine releases, quantification of mRNA expression, cell migration and differentiation assays, immunohistochemical labeling, hematoxylin and eosin, and immunofluorescence staining. Results: P17 activated MRGPRX2 in a dose-dependent manner in b-arrestin recruitment assay. In LAD2 cells, P17 induced calcium and b-hexosaminidase release. Quercetin-and short hairpin RNA-mediated knockdown of MRGPRX2 reduced P17evoked b-hexosaminidase release. In silico and in vitro mutagenesis studies showed that residue Lys 8 of P17 formed a cation-p interaction with the Phe 172 of MRGPRX2 and [Ala 8 ] P17 lost its activity partially. P17 activated LAD2 cells to recruit THP-1 and human monocytes in Transwell migration assay, whereas MRGPRX2-impaired LAD2 cells cannot. In addition, P17-treated LAD2 cells stimulated differentiation of THP-1 and

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“…Human MCs are classified into two subtypes, namely MC T which express high levels of tryptase and MC TC that express both tryptase and chymase in their cytoplasmic granules . In rodents, MCs are classified in two subtypes: mucosal MCs (MMCs) and connective tissue MCs (CTMCs) . MCs become activated upon recognizing IgE bounded allergens and release a wide spectrum of preformed (including chymase, heparin, histamine, and tryptase), newly synthesized mediators mainly lipid mediators such as prostaglandins and leukotrienes and cytokines (eg, TGF‐β, TNF‐α, and VEGF) …”

Section: Mast Cell Biology: Origin Development and Activationmentioning

confidence: 99%

Significance of mast cells in spermatogenesis, implantation, pregnancy, and abortion: Cross talk and molecular mechanisms

Komi

Shafaghat

Haidl

2020

American J Rep Immunol

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Both subsets of MCs including MCTC (tryptase‐positive, chymase‐positive) and MCT (tryptase‐positive, chymase‐negative) are present in the testis and epididymis. Increased number of MCs, higher levels of MC‐released tryptase in testis and seminal plasma of males with fertility problems, and promoting sperm motility in individuals with oligozoospermia after using MC blockers provide evidence that MCs may play a role in male infertility/subfertility disturbances. MC‐released tryptase and histamine contribute to the fibrosis and may disrupt spermatogenesis. MCs not only influence the process of spermatogenesis but also have effects on the function of other testis‐residing cells. MC‐derived histamine may influence the steroidogenesis of Leydig cells by acting through H1R and H2R receptors. Additionally, the interaction between MC‐released ATP and P2X receptors expressed on the peritubular cells may induce the production of the pro‐inflammatory mediators by peritubular cells. Further investigations showed that MCs may be involved in the pathology of female infertility during implantation, pregnancy, and abortion. In the uterus, MCT subtype is abundant in myometrium and adjacent basal layer while MCTC subtype is distributed in all layers. MCs in response to hormones mainly estradiol and progesterone become activated and release a wide range of mediators including histamine, VEGF, proteases, and metalloproteinases (MMPs) that have a role in different stages of pregnancy. An increasing influx of MCs to the cervix during the pregnancy occurs that helps to the physiologic cervical ripening. While MMPs degrade the extracellular matrix (ECM), VEGF modulates neovascularization and histamine influences the embryo implantation. MC‐derived histamine may have a positive effect during implantation due to its participation in tissue remodeling. MC proteases including tryptase and chymase activate the precursors of MMP2 and MMP9 to mediate ECM degradation during the physiologic menstrual cycle. There is a line of evidence that MCs have a role in abortion by releasing TNF‐α.

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Suppression of IgE-Independent Degranulation of Murine Connective Tissue-Type Mast Cells by Dexamethasone

Cited by 9 publications

References 24 publications

Aurora kinase inhibitor tozasertib suppresses mast cell activation in vitro and in vivo

Aurora kinase inhibitor tozasertib suppresses mast cell activation in vitro and in vivo

P17 induces chemotaxis and differentiation of monocytes via MRGPRX2-mediated mast cell–line activation

Significance of mast cells in spermatogenesis, implantation, pregnancy, and abortion: Cross talk and molecular mechanisms

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