The quantity and duration of FcRγ signals determine mast cell degranulation and survival

Yamasaki, Satoshi; Ishikawa, Eri; Kohno, Masayuki; Saito, Takashi

doi:10.1182/blood-2003-08-2944

Cited by 60 publications

(61 citation statements)

References 49 publications

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“…The LPS-stimulated BMMCs were activated with PMA (10 ng͞ml) and ionomycin (1 M), or with IgE͞Ag (anti-DNP IgE and DNP) as described in ref. 49. In the experiments addressing a direct synergistic effect between LPS stimulation and IgE͞Ag stimulation, BMMCs were stimulated with a combination of LPS (10 g͞ml) and IgE͞Ag in vitro for 24 h. The production of cytokines was assessed by ELISA as described in ref.…”

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confidence: 99%

Regulation of allergic airway inflammation through Toll-like receptor 4-mediated modification of mast cell function

Nigo¹,

Yamashita²,

Hirahara³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

136

135

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In a mouse experimental asthma model, the administration of bacterial lipopolysaccharide (LPS), particularly at low doses, enhances the levels of ovalbumin (OVA)-induced eosinophilic airway inflammation. In an effort to clarify the cellular and molecular basis for the LPS effect, we demonstrate that the OVA-induced eosinophilic inflammation in the lung is dramatically increased by the administration of LPS in wild-type mice, whereas such increase was not observed in mast-cell-deficient mice or Toll-like receptor (TLR)4-deficient mice. Adoptive transfer of bone-marrow-derived mast cells (BMMCs) from wild-type, but not from TLR4-deficient, mice restored the increased eosinophilic inflammation in mast-celldeficient mice. Wild-type BMMCs pretreated with LPS in vitro also reconstituted the eosinophilic inflammation. Moreover, in vitro analysis revealed that the treatment of BMMCs with LPS resulted in NF-B activation, sustained up-regulation of GATA1 and -2 expression, and increased the capability to produce IL-5 and -13. Dramatic increases in the expression of IL-5 and -13 and Eotaxin 2 were detected in LPS-treated BMMCs after costimulation with LPS and IgE͞Ag. Overexpression of GATA1, but not GATA2, in MC9 mast cells resulted in increased transcriptional activity of IL-4, -5, and -13. Furthermore, the levels of transcription of Th2 cytokines in BMMCs were decreased by the introduction of small interfering RNA for GATA1. Thus, mast cells appear to control allergic airway inflammation after their activation and modulation through TLR4-mediated induction of GATA1 and subsequent increase in Th2 cytokine production.cytokine ͉ GATA1 ͉ mast cell ͉ lipopolysaccharide ͉ bone-marrow-derived mast cells

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mentioning

confidence: 99%

Regulation of allergic airway inflammation through Toll-like receptor 4-mediated modification of mast cell function

Nigo¹,

Yamashita²,

Hirahara³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

136

135

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“…IgE + Ag could possibly induce extensive crosslinking of the receptors, thereby resulting in the increased phosphorylation of FcRγ-ITAM and further downstream signals. To examine if the cellular output is regulated by the quantity of the FcRγ signal, we expressed CD8 / FcRγ chimera (CD8 / γ) in BMMC from FcRγ −/ − mice and manipulated the strength of the FcRγ signal by anti-CD8 crosslinking (12). The crosslinking of CD8 / γ was sufficient for the induction of mast cell survival and degranulation.…”

Section: Regulation Of Mast Cell Survival Versus Degranulation Througmentioning

confidence: 99%

Progress in Allergy Signal Research on Mast Cells: Signal Regulation of Multiple Mast Cell Responses Through FcεRI

Yamasaki

Saito

2008

J Pharmacol Sci

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Abstract. The crosslinking of FcεRI by IgE and antigen (Ag) on mast cells initiates activation cascades that lead to allergic responses. Although it was thought that IgE binding to FcεRI is a passive "sensitization", recent reports suggest that IgE actively promotes mast cell survival in the absence of Ag. However, it is largely unknown how these distinct responses are delivered through the same receptor, FcεRI, depending on the types of stimli. As an underlying molecular mechanism for the generation of diverse responses through FcεRI, we found that the quantity and the duration of the signal through the FcεRI γ chain (FcRγ) determine different mast cell responses. Furthermore, FcRγ-mediated sustained Erk activation is critical for IgE-induced mast cell survival through autocrine production of IL-3. Transmembrane adaptors LAT and NTAL contribute to the maintenance of prolonged Erk activation through membrane retention of the Ras-activating complex, Grb2-Sos. In this review, the signal regulation for the distinct responses of mast cells through FcεRI are discussed.

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“…Interestingly, however, quantitative variations of receptor aggregation were found to result in qualitative variation in cellular responses. A low level of FcεRI aggregation, induced by incubating mast cells with IgE in the absence of (known) antigen, triggered intracellular signals leading to the secretion of IL-3 or MCP-1, but not to degranulation, whereas a high level of receptor aggregation, induced by incubating with multivalent antigen mast cells sensitized with the same IgE, triggered both degranulation and cytokine secretion (Gonzalez-Espinosa et al, 2003;Yamasaki et al, 2004;Kohno et al, 2005). Molecular mechanisms that enable quantitative differences in receptor aggregation to produce qualitatively different responses remain to be elucidated.…”

Section: Ligand Valency Influence Fcεri-dependent Mast Cell Secretorymentioning

confidence: 99%

Negative Signaling in Fc Receptor Complexes

Daëron

Lesourne

2006

Advances in Immunology

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Cell activation results from the transient displacement of an active balance between positive and negative signaling. This displacement depends in part on the engagement of cell surface receptors by extracellular ligands. Among these are Receptors for the Fc portion of immunoglobulins (FcRs). FcRs are widely expressed by cells of hematopoietic orign. When binding antibodies, FcRs provide these cells with immunoreceptors capable of triggering numerous biological responses in response to specific antigen. FcR-dependent cell activation is regulated by negative signals which are generated together with positive signals within signalosomes that form upon FcR engagement. Many molecules involved in positive signaling, including the FcRβ subunit, the src kinase lyn, the cytosolic adapter Grb2, the transmembrane adapters LAT and NTAL, are indeed also involved in negative signaling. A major player in negative regulation of FcR signaling is the inositol 5-phosphatase SHIP1. Several layers of negative regulation operate sequentially as FcRs are engaged by extracellular ligands of increasing valency. A background protein tyrosine phosphatasedependent negative regulation maintains cells in a « resting » state. SHIP1-dependent negative regulation can be detected as soon as high-affinity FcRs are occupied by antibodies in the absence of antigen. It increases when activating FcRs are engaged by multivalent ligands and, further when FcR aggregation increases, accounting for the bell-shaped dose-response curve observed in excess of ligand. Finally, F-actin skeleton-associated high-molecular weight SHIP1, recruited to phopshorylated ITIMs, concentrates in signaling complexes when activating FcRs are coengaged with inhibitory FcRs by immune complexes. Based on these data, activating and inhibitory FcRs could be used for new therapeutic approaches of immune disorders.

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The quantity and duration of FcRγ signals determine mast cell degranulation and survival

Cited by 60 publications

References 49 publications

Regulation of allergic airway inflammation through Toll-like receptor 4-mediated modification of mast cell function

Regulation of allergic airway inflammation through Toll-like receptor 4-mediated modification of mast cell function

Progress in Allergy Signal Research on Mast Cells: Signal Regulation of Multiple Mast Cell Responses Through FcεRI

Negative Signaling in Fc Receptor Complexes

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