Kit and FcϵRI mediate unique and convergent signals for release of inflammatory mediators from human mast cells

Hundley, Thomas R.; Gilfillan, Alasdair M.; Tkaczyk, Christine; Andrade, Marcus V.; Metcalfe, Dean D.; Beaven, Michael A.

doi:10.1182/blood-2004-02-0631

Cited by 148 publications

(174 citation statements)

References 66 publications

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“…In this study, we found that Rcan1 deficiency does not impose upon the activation of the MAPK family members JNK, p38, and ERK, nor does it impact upon Akt/PI3K-signaling activity (41). These results are consistent with a previous report showing that cyclosporine A had no effect on SCF-mediated JNK and p38 (40).…”

Section: Discussionsupporting

confidence: 92%

Calcineurin–Rcan1 Interaction Contributes to Stem Cell Factor–Mediated Mast Cell Activation

Li²,

MacNeil³

et al. 2013

The Journal of Immunology

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The receptor for stem cell factor (SCF) is expressed on mast cells and hematopoietic progenitors. SCF-induced signaling pathways remain incompletely defined. In this study, we identified calcineurin and regulator of calcineurin 1 (Rcan1) as novel components in SCF signaling. Calcineurin activity was induced in SCF-stimulated primary mouse and human mast cells. NFAT was activated by SCF in bone marrow–derived mast cells (BMMCs) and mouse bone marrow cells, which contain hematopoietic progenitors. SCF-mediated activation also induced expression of Rcan1 in BMMCs. Rcan1-deficient BMMCs showed increased calcineurin activity and enhanced transcriptional activity of NF-κB and NFAT, resulting in increased IL-6 and TNF production following SCF stimulation. These results suggest that Rcan1 suppresses SCF-induced activation of calcineurin and NF-κB. We further demonstrated that SCF-induced Rcan1 expression is dependent on the transcription factor early growth response 1 (Egr1). Interestingly, SCF-induced Egr1 was also suppressed by Rcan1, suggesting a negative regulatory loop between Egr1 and Rcan1. Together, our findings revealed that calcineurin contributes to SCF-induced signaling, leading to NFAT activation, which, together with NF-κB and Egr1, is suppressed by Rcan1. Considering the wide range of biological functions of SCF, these novel regulatory mechanisms in SCF signaling may have broad implications.

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Section: Discussionsupporting

confidence: 92%

Calcineurin–Rcan1 Interaction Contributes to Stem Cell Factor–Mediated Mast Cell Activation

Li²,

MacNeil³

et al. 2013

The Journal of Immunology

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“…In contrast to murine mast cells, antigen was not able to induce STAT5 phosphorylation in human mast cells (18). This discrepancy probably reflects different signaling pathways in human and murine mast cells.…”

mentioning

confidence: 75%

“…Traditionally, analysis of signaling in human basophils and mast cells has been performed using Western blot techniques (18,25). Recently, it has been demonstrated that flow cytometry can generate qualitative results concerning dose responses and kinetics of signaling molecules similar and complementary to the data obtained with blotting techniques (19,(26)(27)(28).…”

Section: Discussionmentioning

confidence: 99%

STAT5 in human basophils: IL‐3 is required for its FcεRI‐mediated phosphorylation

Verweij

Sabato

Nullens

et al. 2011

Cytometry Part B Clinical

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“…As shown in mast cell deficient KIT-mutant, W/W v , W/W sh , and SCF-mutant, Sl/Sl d , mice, signaling through KIT is crucial for correct development, growth, differentiation, survival, and homing of mast cells [33]. Consistently, in in vitro studies with both human and mouse mast cells, KIT activation is not abled by itself to induce mast cell degranulation, but can enhance mast cell degranulation and cytokine production in combination with antigenic stimulation [34,35]. In contrast to FcεRI, KIT is a single chain receptor with intrinsic tyrosine kinase activity, although it shares downstream signaling proteins in common with the FcεRI-dependent cascade.…”

Section: Kit Enhances Fcεri-mediated Activationmentioning

confidence: 99%

Mast cell activation: A complex interplay of positive and negative signaling pathways

Sibilano¹,

2014

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Mast cells regulate the immunological responses causing allergy and autoimmunity, and contribute to the tumor microenvironment through generation and secretion of a broad array of preformed, granule-stored and de novo synthesized bioactive compounds. The release and production of mast cell mediators is the result of a coordinated signaling machinery, followed by the FcεRI and FcγR antigen ligation. In this review, we present the latest understanding of FcεRI and FcγR signaling, required for the canonical mast cell activation during allergic responses and anaphylaxis. We then describe the cooperation between the signaling of FcR and other recently characterized membrane-bound receptors (i.e., IL-33R and thymic stromal lymphopoietin receptor) and their role in the chronic settings, where mast cell activation is crucial for the development and the sustainment of chronic diseases, such as asthma or airway inflammation. Finally, we report how the FcR activation could be used as a therapeutic approach to treat allergic and atopic diseases by mast cell inactivation. Understanding the magnitude and the complexity of mast cell signaling is necessary to identify the mechanisms underlying the potential effector and regulatory roles of mast cells in the biology and pathology of those disease settings in which mast cells are activated.Keywords: FcεRI r FcγR r IL-33 r mast cells r TSLP IntroductionMast cells originate in the BM from a lineage-specific multipotent hematopoietic progenitor, circulate as CD34 + precursors until they migrate to tissues and mature into effector cells in the proximity of organs and blood vessels. Mast cells respond to antigenic stimulation through the cross-linking of immunoglobulin E (IgE) bound to high-affinity receptors for IgE (FcεRI) and the activation of the FcγR after IgG binding (reviewed in [1,2]). Upon activation, mast cells release either preformed, granule-stored mediators, such as histamine and proteases, or newly generated mediators, such as eicosanoids, cytokines, and chemokines [3]. Although the basic molecular mechanisms of Ig:Fc activation have been extensively studied in the past 15 years [4][5][6], new molecules regulating the Correspondence: Dr. Barbara Frossi e-mail: barbara.frossi@uniud.it FcR-signaling cascades have recently been characterized, suggesting not only a still vivid interest in the field of mast cell activation and signaling, but also in identifying putative new therapeutic targets for intervention in mast cell dependent disorders. This review will focus on three aspects of mast cell activation/function. First, we give an essential but complete overview of the FcR-mediated activation in mast cells and report on recent advances in IgE-and IgG-mediated signaling. For clarity, we will dissect and analyze the signals derived from each pathway, with particular attention to the newly identified positive or negative molecular players describing -when possible -their implication toward degranulation and cytokine production. Second, we highlight the growing interest aroun...

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Kit and FcϵRI mediate unique and convergent signals for release of inflammatory mediators from human mast cells

Cited by 148 publications

References 66 publications

Calcineurin–Rcan1 Interaction Contributes to Stem Cell Factor–Mediated Mast Cell Activation

Calcineurin–Rcan1 Interaction Contributes to Stem Cell Factor–Mediated Mast Cell Activation

STAT5 in human basophils: IL‐3 is required for its FcεRI‐mediated phosphorylation

Mast cell activation: A complex interplay of positive and negative signaling pathways

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