Dnmt3arestrains mast cell inflammatory responses

DNA methylation and specifically the DNA methyltransferase enzyme DNMT3A are involved in the pathogenesis of a variety of hematological diseases and in regulating the function of immune cells. Although altered DNA methylation patterns and mutations inDNMT3Acorrelate with mast cell proliferative disorders in humans, the role of DNA methylation in mast cell biology is not understood. By using mast cells lackingDnmt3a, we found that this enzyme is involved in restraining mast cell responses to acute and chronic stimuli, both in vitro and in vivo. The exacerbated mast cell responses observed in the absence ofDnmt3awere recapitulated or enhanced by treatment with the demethylating agent 5-aza-2′-deoxycytidine as well as by down-modulation ofDnmt1expression, further supporting the role of DNA methylation in regulating mast cell activation. Mechanistically, these effects were in part mediated by the dysregulated expression of the scaffold protein IQGAP2, which is characterized by the ability to regulate a wide variety of biological processes. Altogether, our data demonstrate that DNMT3A and DNA methylation are key modulators of mast cell responsiveness to acute and chronic stimulation.

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SWAP-70 Regulates c-kit-Induced Mast Cell Activation, Cell-Cell Adhesion, and Migration

Molecular and Cellular Biology ◽

10.1128/mcb.24.23.10277-10288.2004 ◽

2004 ◽

Vol 24 (23) ◽

pp. 10277-10288 ◽

Cited By ~ 51

Author(s):

Raja Rajeswari Sivalenka ◽

Rolf Jessberger

Keyword(s):

Mast Cell ◽

Cell Adhesion ◽

Mast Cells ◽

Cell Activation ◽

Mast Cell Activation ◽

Calcium Flux ◽

Mutant Cells

ABSTRACT SWAP-70, an unusual phosphatidylinositol-3-kinase-dependent protein that interacts with the RhoGTPase Rac, is highly expressed in mast cells. Cultured bone marrow mast cells (BMMC) from SWAP-70−/− mice are reduced in FcεRI-triggered degranulation. This report describes the hitherto-unknown role of SWAP-70 in c-kit receptor signaling, a key proliferation and differentiation pathway in mast cells. Consistent with the role of Rac in cell motility and regulation of the actin cytoskeleton, mutant cells show abnormal actin rearrangements and are deficient in migration in vitro and in vivo. SWAP-70−/− BMMC are impaired in calcium flux, in proper translocation and activity of Akt kinase (required for mast cell activation and survival), and in translocation of Rac1 and Rac2 upon c-kit stimulation. Adhesion to fibronectin is reduced, but homotypic cell association induced through c-kit is strongly increased in SWAP-70−/− BMMC. Homotypic association requires extracellular Ca2+ and depends on the integrin αLβ2 (LFA-1). ERK is hyperactivated upon c-kit signaling in adherent and dispersed mutant cells. Together, we suggest that SWAP-70 is an important regulator of specific effector pathways in c-kit signaling, including mast cell activation, migration, and cell adhesion.

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Role of mucosal mast cells in early vascular permeability changes of intestinal DTH reaction in the rat

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.1998.274.5.g832 ◽

1998 ◽

Vol 274 (5) ◽

pp. G832-G839 ◽

Cited By ~ 3

Author(s):

Aletta D. Kraneveld ◽

Thea Muis ◽

Andries S. Koster ◽

Frans P. Nijkamp

Keyword(s):

Mast Cell ◽

Mast Cells ◽

Cell Activation ◽

Vascular Leakage ◽

Mast Cell Activation ◽

Mucosal Mast Cell ◽

Mucosal Mast Cells

Previously, it was shown that depletion and stabilization of the mucosal mast cell around the time of challenge were very effective in reducing delayed-type hypersensitivity (DTH) reactions in the small intestine of the rat. The role of mucosal mast cells in the early component of intestinal DTH reaction was further investigated in this study. In vivo small intestinal vascular leakage and serum levels of rat mast cell protease II (RMCP II) were determined within 1 h after intragastric challenge of rats that had been sensitized with dinitrobenzene 5 days before. A separate group of rats was used to study vasopermeability in isolated vascularly perfused small intestine after in vitro challenge. To investigate the effects of mast cell stabilization on the early events of the DTH reaction, doxantrazole was used. The influence of sensory nerves was studied by means of neonatal capsaicin-induced depletion of sensory neuropeptides. Within 1 h after challenge, a significant increase in vascular permeability was found in vivo as well as in vitro. This was associated with a DTH-specific increase in RMCP II in the serum, indicating mucosal mast cell activation. In addition, doxantrazole treatment and caspaicin pretreatment resulted in a significant inhibition of the DTH-induced vascular leakage and an increase in serum RMCP II. These findings are consistent with an important role for mucosal mast cells in early vascular leakage changes of intestinal DTH reactions. In addition, sensory nervous control of mucosal mast cell activation early after challenge is demonstrated.

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Mast cell–mediated inflammatory responses require the α2β1 integrin

Blood ◽

10.1182/blood-2003-08-2978 ◽

2004 ◽

Vol 103 (6) ◽

pp. 2214-2220 ◽

Cited By ~ 54

Author(s):

Brian T. Edelson ◽

Zhengzhi Li ◽

Loretta K. Pappan ◽

Mary M. Zutter

Keyword(s):

Mast Cell ◽

Mast Cells ◽

Cell Biology ◽

Cell Activation ◽

Inflammatory Responses ◽

Neutrophil Migration ◽

Mast Cell Activation ◽

Integrin Subunit ◽

Peritoneal Mast Cells ◽

Α2β1 Integrin

Abstract Although the α2β1 integrin is widely expressed and has been extensively studied, it has not been previously implicated in mast cell biology. We observed that α2 integrin subunit-deficient mice exhibited markedly diminished neutrophil and interleukin-6 responses during Listeria monocytogenes– and zymosan-induced peritonitis. Since exudative neutrophils of wild-type mice expressed little α2β1 integrin, it seemed unlikely that this integrin mediated neutrophil migration directly. Here, we demonstrate constitutive α2β1 integrin expression on peritoneal mast cells. Although α2-null mice contain normal numbers of peritoneal mast cells, these α2-null cells do not support in vivo mast cell–dependent inflammatory responses. We conclude that α2β1 integrin provides a costimulatory function required for mast cell activation and cytokine production in response to infection.

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Anti-Inflammatory Effects of Novel Glycyrrhiza Variety Wongam In Vivo and In Vitro

Applied Sciences ◽

10.3390/app112210822 ◽

2021 ◽

Vol 11 (22) ◽

pp. 10822

Author(s):

Yun-Mi Kang ◽

Jeonghoon Lee ◽

Wonnam Kim ◽

Jong-Sik Jin ◽

Jong-Hyun Lee ◽

...

Keyword(s):

Mast Cell ◽

Proinflammatory Cytokines ◽

Cell Activation ◽

Inflammatory Responses ◽

Immunoglobulin E ◽

Mast Cell Activation ◽

In Vivo Model ◽

Cell Surface Antigens

Licorice is the common name of Glycyrrhiza species, which is an important plant for edible and medicinal purposes; however, Glycyrrhiza resources have become limited because of desertification, depletion of natural resources, and environmental restrictions. For this reason, a novel Glycyrrhiza variety named Wongam, a hybrid of G. glabra and G. uralensis, was developed by the Korea Rural Development Administration. To elucidate the antiallergic inflammatory effects of Wongam, we investigated its effects using a compound-48/80-induced anaphylaxis in vivo model and PMA/A23187-stimulated HMC-1 cells and immunoglobulin E (IgE)/DNP-stimulated RBL-2H3 cells in in vitro models. Wongam treatment reduced mortality and serum IgE levels and downregulated proinflammatory cytokines and chemokines in a compound-48/80-induced anaphylaxis mouse model. Wongam decreased histamine release and the expression of proinflammatory cytokines in HMC-1 and RBL-2H3 cells. Wongam treatment downregulated the expression of chemokines, T helper 2 cytokines, and cell surface antigens in PMA/A23187-stimulated HMC-1 cells. We confirmed that these effects were associated with the inhibition of the MAPK and NF-κB signaling pathways by Wongam. The present study suggests that Wongam ameliorates mast-cell-mediated allergic inflammatory responses by reducing mast cell activation and may serve as an effective agent for the prevention and treatment of allergic inflammatory responses.

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Role of ?-chemokines in mast cell activation and type I hypersensitivity reactions in the conjunctiva: in vivo and in vitro studies

Immunological Reviews ◽

10.1111/j.1600-065x.2007.00521.x ◽

2007 ◽

Vol 217 (1) ◽

pp. 96-104 ◽

Cited By ~ 9

Author(s):

Frederick Beer ◽

Chuan-Hui Kuo ◽

Kei Morohoshi ◽

James Goodliffe ◽

Peter Munro ◽

...

Keyword(s):

Mast Cell ◽

Cell Activation ◽

In Vitro Studies ◽

Mast Cell Activation ◽

Type I ◽

Hypersensitivity Reactions ◽

Type I Hypersensitivity

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Basic and clinical immunology – 3022. Inhibitory action of fexofenadine hydrochloride on mast cell activation in vitro

World Allergy Organization Journal ◽

10.1186/1939-4551-6-s1-p198 ◽

2013 ◽

Vol 6 ◽

pp. P198

Author(s):

Miyuki Suzuki ◽

Atsuko Furuta ◽

Kazuhito Asano ◽

Harumi Suzaki

Keyword(s):

Mast Cell ◽

Clinical Immunology ◽

Inhibitory Action ◽

Cell Activation ◽

Mast Cell Activation

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Anti-Allergic Potential of Cinnamaldehyde via the Inhibitory Effect of Histidine Decarboxylase (HDC) Producing Klebsiella pneumonia

Molecules ◽

10.3390/molecules25235580 ◽

2020 ◽

Vol 25 (23) ◽

pp. 5580

Author(s):

Lorina I. Badger-Emeka ◽

Promise Madu Emeka ◽

Krishnaraj Thirugnanasambantham ◽

Hairul Islam M. Ibrahim

Keyword(s):

Mast Cell ◽

Cell Activation ◽

Histidine Decarboxylase ◽

Cell Model ◽

In Vitro Study ◽

Inhibitory Effect ◽

Mast Cell Activation ◽

Klebsiella Pneumonia ◽

Immunological Disorder

Allergy is an immunological disorder that develops in response to exposure to an allergen, and histamines mediate these effects via histidine decarboxylase (HDC) activity at the intracellular level. In the present study, we developed a 3D model of Klebsiella pneumoniae histidine decarboxylase (HDC) and analyzed the HDC inhibitory potential of cinnamaldehyde (CA) and subsequent anti-allergic potential using a bacterial and mammalian mast cell model. A computational and in vitro study using K. pneumonia revealed that CA binds to HDC nearby the pyridoxal-5′-phosphate (PLP) binding site and inhibited histamine synthesis in a bacterial model. Further study using a mammalian mast cell model also showed that CA decreased the levels of histamine in the stimulated RBL-2H3 cell line and attenuated the release of β-hexoseaminidase and cell degranulation. In addition, CA treatment also significantly suppressed the levels of pro-inflammatory cytokines TNF-α and IL-6 and the nitric oxide (NO) level in the stimulated mast cells. A gene expression and Western blotting study revealed that CA significantly downregulated the expressions of MAPKp38/ERK and its downstream pro-allergic mediators that are involved in the signaling pathway in mast cell cytokine synthesis. This study further confirms that CA has the potential to attenuate mast cell activation by inhibiting HDC and modifying the process of allergic disorders.

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