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

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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Effect of arginine analogues on rat hind paw oedema and mast cell activation in vitro

European Journal of Pharmacology ◽

10.1016/0014-2999(94)90698-x ◽

1994 ◽

Vol 257 (1-2) ◽

pp. 87-93 ◽

Cited By ~ 28

Author(s):

Cleria M.M. Giraldelo ◽

Aldete Zappellini ◽

Marcelo N. Muscará ◽

Iara M.S. De Luca ◽

Stephen Hyslop ◽

...

Keyword(s):

Mast Cell ◽

Cell Activation ◽

Mast Cell Activation ◽

Paw Oedema

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Platelet activation responses in vitro to human mast cell activation

British Journal of Haematology ◽

10.1046/j.1365-2141.1999.01478.x ◽

1999 ◽

Vol 106 (1) ◽

pp. 208-215 ◽

Cited By ~ 3

Author(s):

Gardiner ◽

Harrison ◽

Chavda ◽

Mackie ◽

Machin

Keyword(s):

Mast Cell ◽

Platelet Activation ◽

Cell Activation ◽

Mast Cell Activation ◽

Human Mast Cell

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Increased Severity of Local and Systemic Anaphylactic Reactions in Gp49b1-Deficient Mice

Journal of Experimental Medicine ◽

10.1084/jem.194.2.227 ◽

2001 ◽

Vol 194 (2) ◽

pp. 227-234 ◽

Cited By ~ 53

Author(s):

Massoud Daheshia ◽

Daniel S. Friend ◽

Michael J. Grusby ◽

K. Frank Austen ◽

Howard R. Katz

Keyword(s):

Mast Cell ◽

Cell Activation ◽

Mast Cell Activation ◽

Critical Question ◽

Increased Sensitivity ◽

Antibody Levels ◽

Deficient Mice

gp49B1 is an immunoglobulin (Ig) superfamily member that inhibits FcεRI-induced mast cell activation when the two receptors are coligated with antibodies in vitro. The critical question of in vivo function of gp49B1 is now addressed in gene-disrupted mice. gp49B1-deficient mice exhibited a significantly increased sensitivity to IgE-dependent passive cutaneous anaphylaxis as assessed by greater tissue swelling and mast cell degranulation in situ. Importantly, by the same criteria, the absence of gp49B1 also resulted in a lower threshold for antigen challenge in active cutaneous anaphylaxis, in which the antigen-specific antibody levels were comparable in gp49B1-deficient and sufficient mice. Moreover, the absence of gp49B1 resulted in a significantly greater and faster death rate in active systemic anaphylaxis. These results indicate that gp49B1 innately dampens adaptive immediate hypersensitivity responses by suppressing mast cell activation in vivo. In addition, this study provides a new concept and target for regulation of allergic disease susceptibility and severity.

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IgE Enhances Mouse Mast Cell FcεRI Expression In Vitro and In Vivo: Evidence for a Novel Amplification Mechanism in IgE-dependent Reactions

Journal of Experimental Medicine ◽

10.1084/jem.185.4.663 ◽

1997 ◽

Vol 185 (4) ◽

pp. 663-672 ◽

Cited By ~ 295

Author(s):

Masao Yamaguchi ◽

Chris S. Lantz ◽

Hans C. Oettgen ◽

Ildy M. Katona ◽

Tony Fleming ◽

...

Keyword(s):

Mast Cell ◽

Mast Cells ◽

Cell Activation ◽

Immunoglobulin E ◽

Specific Antigen ◽

Mast Cell Activation ◽

Proinflammatory Mediators ◽

Mouse Mast Cell

The binding of immunoglobulin E (IgE) to high affinity IgE receptors (FcεRI) expressed on the surface of mast cells primes these cells to secrete, upon subsequent exposure to specific antigen, a panel of proinflammatory mediators, which includes cytokines that can also have immunoregulatory activities. This IgE- and antigen-specific mast cell activation and mediator production is thought to be critical to the pathogenesis of allergic disorders, such as anaphylaxis and asthma, and also contributes to host defense against parasites. We now report that exposure to IgE results in a striking (up to 32-fold) upregulation of surface expression of FcεRI on mouse mast cells in vitro or in vivo. Moreover, baseline levels of FcεRI expression on peritoneal mast cells from genetically IgE-deficient (IgE −/−) mice are dramatically reduced (by ∼83%) compared with those on cells from the corresponding normal mice. In vitro studies indicate that the IgE-dependent upregulation of mouse mast cell FcεRI expression has two components: an early cycloheximide-insensitive phase, followed by a later and more sustained component that is highly sensitive to inhibition by cycloheximide. In turn, IgE-dependent upregulation of FcεRI expression significantly enhances the ability of mouse mast cells to release serotonin, interleukin-6 (IL-6), and IL-4 in response to challenge with IgE and specific antigen. The demonstration that IgE-dependent enhancement of mast cell FcεRI expression permits mast cells to respond to antigen challenge with increased production of proinflammatory and immunoregulatory mediators provides new insights into both the pathogenesis of allergic diseases and the regulation of protective host responses to parasites.

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Dnmt3arestrains mast cell inflammatory responses

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1616420114 ◽

2017 ◽

Vol 114 (8) ◽

pp. E1490-E1499 ◽

Cited By ~ 44

Author(s):

Cristina Leoni ◽

Sara Montagner ◽

Andrea Rinaldi ◽

Francesco Bertoni ◽

Sara Polletti ◽

...

Keyword(s):

Dna Methylation ◽

Mast Cell ◽

Cell Biology ◽

Dna Methyltransferase ◽

Cell Activation ◽

Inflammatory Responses ◽

Mast Cell Activation ◽

Cell 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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Characterizing the inhibitory action of zinc oxide nanoparticles on allergic-type mast cell activation

Molecular Immunology ◽

10.1016/j.molimm.2015.02.021 ◽

2015 ◽

Vol 66 (2) ◽

pp. 139-146 ◽

Cited By ~ 13

Author(s):

B.N. Feltis ◽

A. Elbaz ◽

P.F.A. Wright ◽

G.A. Mackay ◽

T.W. Turney ◽

...

Keyword(s):

Zinc Oxide ◽

Mast Cell ◽

Zinc Oxide Nanoparticles ◽

Inhibitory Action ◽

Cell Activation ◽

Mast Cell Activation ◽

Oxide Nanoparticles

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Borrelia burgdorferiSpirochetes Induce Mast Cell Activation and Cytokine Release

Infection and Immunity ◽

10.1128/iai.67.3.1107-1115.1999 ◽

1999 ◽

Vol 67 (3) ◽

pp. 1107-1115 ◽

Cited By ~ 22

Author(s):

Jeffrey Talkington ◽

Steven P. Nickell

Keyword(s):

Mast Cell ◽

Mast Cells ◽

Cell Activation ◽

Cell Types ◽

Host Cells ◽

Mast Cell Activation ◽

Cytokine Release ◽

Necrosis Factor Alpha ◽

Tnf Α

ABSTRACT The Lyme disease spirochete, Borrelia burgdorferi, is introduced into human hosts via tick bites. Among the cell types present in the skin which may initially contact spirochetes are mast cells. Since spirochetes are known to activate a variety of cell types in vitro, we tested whether B. burgdorferi spirochetes could activate mast cells. We report here that freshly isolated rat peritoneal mast cells or mouse MC/9 mast cells cultured in vitro with live or freeze-thawed B. burgdorferi spirochetes undergo low but detectable degranulation, as measured by [5-3H] hydroxytryptamine release, and they synthesize and secrete the proinflammatory cytokine tumor necrosis factor alpha (TNF-α). In contrast to findings in previous studies, where B. burgdorferi-associated activity was shown to be dependent upon protein lipidation, mast cell TNF-α release was not induced by either lipidated or unlipidated recombinant OspA. This activity was additionally shown to be protease sensitive and surface expressed. Finally, comparisons of TNF-α-inducing activity in known low-, intermediate-, and high-passage B. burgdorferi B31 isolates demonstrated passage-dependent loss of activity, indicating that the activity is probably plasmid encoded. These findings document the presence in low-passage B. burgdorferi spirochetes of a novel lipidation-independent activity capable of inducing cytokine release from host cells.

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Abstract 459: Vascular Neuropeptide Y Contributes to Atherosclerotic Plaque Progression and Perivascular Mast Cell Activation

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.34.suppl_1.459 ◽

2014 ◽

Vol 34 (suppl_1) ◽

Author(s):

H Maxime Lagraauw ◽

Marijke M Westra ◽

Martine Bot ◽

Anouk Wezel ◽

Peter J Santbrink ◽

...

Keyword(s):

Mast Cell ◽

Neuropeptide Y ◽

Atherosclerotic Plaque ◽

Cell Activation ◽

Lentiviral Vector ◽

Cell Types ◽

Mast Cell Activation ◽

Plaque Progression ◽

Plaque Development

Aim: Neuropeptide Y is an abundantly expressed neurotransmitter capable of modulating both immune and metabolic responses related to the development of atherosclerosis. NPY receptors are expressed by a number of vascular wall cell types, among which mast cells. However, the direct effects of NPY on perivascular inflammation and atherosclerotic plaque progression remain to be investigated. In this study we thus aimed to determine whether NPY is expressed in atherosclerotic plaques and to establish its role in atherosclerotic plaque development. Methods and Results: NPY expression was seen to be increased up to 2-fold in unstable human endarterectomy plaques, as compared to stable plaques (p<0.05, n=9-12), and to be significantly upregulated during lesion progression in apoE -/- mice (p<0.001, n=4 per timepoint). In apoE -/- mice overexpression of NPY in the carotid artery by means of local application of a lentiviral vector significantly increased atherosclerotic plaque size compared to controls (54 ± 9 *10 3 μm 2 versus 31 ± 6 *10 3 μm 2 , P<0.05, n=12), while plaque composition was unaffected. Interestingly, perivascular mast cell activation was significantly higher in the NPY-overexpressing mice (48.1 ± 4.0 % versus 30.2 ± 6.0 %, P<0.05), suggesting that NPY may impact plaque progression in part via mast cell activation. Furthermore, in vitro NPY-induced murine mast cell activation resulted in the release of pro-atherogenic mediators including IL-6 (515.0 ± 12.5 pg/ml vs. 87.5 ± 5.0 pg/ml) and tryptase. Conclusions: Our data show that NPY expression is increased during atherogenesis and in particular in unstable plaques. Furthermore, perivascular overexpression of NPY promoted plaque development and perivascular mast cell activation, suggestive of a role for NPY-induced mast cell activation in lesion progression.

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Abstract 476: Mast Cell--Mediated Neutrophil Influx Enhances Plaque Progression

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.34.suppl_1.476 ◽

2014 ◽

Vol 34 (suppl_1) ◽

Author(s):

Anouk Wezel ◽

H Maxime Lagraauw ◽

Daniël van der Velden ◽

Saskia C de Jager ◽

Paul H Quax ◽

...

Keyword(s):

Mast Cell ◽

Mast Cells ◽

Cell Activation ◽

Neutrophil Migration ◽

Fold Increase ◽

Mast Cell Activation ◽

Neutrophil Influx ◽

Migration Assay ◽

Cell Activator

Rationale: Activated mast cells have been identified in atherosclerotic plaques. As mast cells have the ability to release chemokines that mediate leukocyte fluxes, we propose that activated mast cells play a pivotal role in leukocyte recruitment during atherosclerosis. Methods and Results: Diet fed B-cell deficient apoE-/-muChain mice, which lack endogenous IgE, received 6 IgE or PBS injections over a period of 8 weeks. Mast cells in the aortic root were significantly more activated after IgE treatment and concomitantly, we detected an increase in plaque size (P=0.050). Intriguingly, a striking increase in the amount of perivascular neutrophils was observed in IgE treated mice (control: 57.6 ± 10.6 neutrophils/mm2 tissue; IgE: 183.0 ± 38.7 neutrophils/mm2 tissue; P=0.01). In order to investigate if activated mast cells can directly attract neutrophils, we injected C57Bl/6 or mast cell deficient Kit(W-sh/W-sh) mice intra-peritoneal with the mast cell activator 48/80. Interestingly, mast cell activation led to a massive neutrophil influx into the peritoneal cavity, while neutrophil numbers in mast cell deficient mice remained unaffected. To confirm these findings, we performed an in vitro migration assay. Indeed, supernatant of activated mast cells caused a 3-fold increase in neutrophil migration (P=0.007). Moreover, addition of anti-CXCR2 to the neutrophils resulted in a major reduction of migration (P=0.03) whereas anti-CXCR4 did not reduce migration significantly. Conclusions: Chemokines released from activated perivascular mast cells induce neutrophil recruitment to the atherosclerotic plaque, thereby aggravating the inflammatory response.

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