Involvement of Bruton's Tyrosine Kinase in Fc RI-dependent Mast Cell Degranulation and Cytokine Production (original) (raw)
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Summary We investigated the role of Bruton's tyrosine kinase (Btk) in Fc e RI-dependent activation of mouse mast cells, using xid and btk null mutant mice. Unlike B cell development, mast cell de- velopment is apparently normal in these btk mutant mice. However, mast cells derived from these mice exhibited significant abnormalities in Fc e RI-dependent function. xid mice primed with anti-dinitrophenyl monoclonal IgE antibody exhibited mildly diminished early-phase and severely blunted late-phase anaphylactic reactions in response to antigen challenge in vivo. Consistent with this finding, cultured mast cells derived from the bone marrow cells of xid or btk null mice exhibited mild impairments in degranulation, and more profound defects in the production of several cytokines, upon Fc e RI cross-linking. Moreover, the transcriptional ac- tivities of these cytokine genes were severely reduced in Fc e RI-stimulated btk mutant mast cells. The specificity of these effects of btk muta...
Functions of Bruton's tyrosine kinase in mast and B cells
Journal of leukocyte biology, 1999
Bruton's tyrosine kinase (Btk) plays crucial roles in B cell differentiation as well as mast cell activation through the high-affinity IgE receptor (FcepsilonRI). Defects in the btk gene lead to agammaglobulinemia (XLA) in humans and X-linked immunodeficiency (xid) in mice. Mast cells from xid and btk null mice exhibit mild defects in degranulation and severe impairments in the production of proinflammatory cytokines upon FcepsilonRI cross-linking. Recent studies demonstrated the role of Btk in a sustained increase in intracellular calcium concentrations in response to antigen receptor stimulation. Btk is also involved in the activation of stress-activated protein kinases, JNK/SAPK1/2, and thereby regulates c-Jun and other transcription factors that are important in cytokine gene activation. Regulation of the JNK/SAPK activation pathway by Btk may be related to the proapoptotic function of Btk in the programmed cell death in these hematopoietic cells.
Mast cell activation: A complex interplay of positive and negative signaling pathways
European Journal of Immunology, 2014
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.
Negative signals from FcεRI engagement attenuate mast cell functions
Archivum Immunologiae et Therapiae Experimentalis, 2007
Mast cells have long been recognized as the critical tissue-based effector cells in IgE-mediated allergic diseases. Ligation of the high-affinity receptor for IgE (FcεRI), constitutively expressed on mast cells, promotes cell activation and immediate release and production of pro-inflammatory mediators. Besides these positive signals, FcεRI aggregation has recently been understood to generate negative intracellular signals capable of limiting mast cell functional responses. This review is aimed at providing a summary of the mechanisms through which FcεRI engagement can generate negative signals and regulate mast-cell function. Similar mechanisms are employed by other receptors expressed by immune cells, such as T cell and B cell receptors, pointing to a general concept in negative immunoreceptor signaling.
Protein tyrosine phosphatase ε is a negative regulator of FcεRI-mediated mast cell responses
Modulation of mast-cell activation may provide novel ways to control allergic diseases. Here, we show that protein tyrosine phosphatase e (PTPe; Ptpre) plays key regulatory roles during mast-cell activation mediated by the high-affinity IgE receptor (FceRI). Bone marrow-derived mast cells (BMMC) from Ptpre ) ⁄ ) mice exhibited enhanced FceRI-induced Ca 2+ mobilization and mitogen-activated protein kinase (MAPK) (JNK and p38) activation, and showed corresponding enhancement of evoked degranulation and cytokine production, but not leukotriene production. Examination of proteins linking tyrosine kinase activation and Ca 2+ mobilization revealed that the absence of PTPe leads to increased phosphorylation of the linker for activation of T cells and SH2 domain-containing leucocyte phosphoproteins of 76 kDa, but not Grb2-associated binder-2 (Gab2). Because Gab2 is considered to be situated downstream of Fyn kinase, we reasoned that Fyn may not be a target of PTPe. In the event, Syk but not Lyn was hyperphosphorylated in PTPe-deficient BMMC. Thus, PTPe most likely exerts its effects at the level of Syk, inhibiting downstream events including phosphorylation of SLP-76 and linker of activated T cells and mobilization of Ca 2+ . Consistent with the in vitro data, antigen-and IgE-mediated passive systemic anaphylactic reactions were augmented in Ptpre ) ⁄ ) mice. Given that the number of mast cells is unchanged in these mice, this observation most likely reflects alterations of mast cell-autonomous signalling events. These data suggest that PTPe negatively regulates FceRImediated signalling pathways and thus constitutes a novel target for ameliorating allergic conditions.
Positive and Negative Regulation of Mast Cell Activation by Lyn via the Fc RI
The Journal of Immunology, 2005
Aggregation of the high affinity receptor for IgE (Fc⑀RI) induces activation of mast cells. In this study we show that upon low intensity stimulation of Fc⑀RI with monomeric IgE, IgE plus anti-IgE, or IgE plus low Ag, Lyn (a Src family kinase) positively regulates degranulation, cytokine production, and survival, whereas Lyn works as a negative regulator of high intensity stimulation with IgE plus high Ag. Low intensity stimulation suppressed Lyn kinase activity and its association with Fc⑀RI  subunit, whereas high intensity stimulation enhanced Lyn activity and its association with Fc⑀RI . The latter induced much higher levels of Fc⑀RI  phosphorylation and Syk activity than the former. Downstream positive signaling molecules, such as Akt and p38, were positively and negatively regulated by Lyn upon low and high intensity stimulations, respectively. In contrast, the negative regulators, SHIP and Src homology 2 domain-containing protein tyrosine phosphatase-1, interacted with Fc⑀RI , and their phosphorylation was controlled by Lyn. Therefore, we conclude that Lyn-mediated positive vs negative regulation depends on the intensity of the stimuli. Studies of mutant Fc⑀RI  showed that Fc⑀RI  subunit-ITAM (ITAM motif) regulates degranulation and cytokine production positively and negatively depending on the intensity of Fc⑀RI stimulation. Furthermore, Lyn-mediated negative regulation was shown to be exerted via the Fc⑀RI -ITAM. The Journal of Immunology, 2005, 175: 6885-6892. Abbreviations used in this paper: PTK, protein tyrosine kinase; BMMC, bone marrow-derived mast cell; Csk, C-terminal Src kinase; HC, highly cytokinergic; SCF, stem cell factor; SH, Src homology; SHP-1, SH2-containing protein tyrosine phosphatase-1; wt, wild type.
A current understanding of FcɛRI-dependent mast cell activation
Current Allergy and Asthma Reports, 2008
Mast cell activation via the high-affinity immunoglobulin (Ig) E receptor Fc RI is a topic of extensive investigation with therapeutic potential in allergic disease. The protein tyrosine kinases Fyn, Lyn, and Syk are intimately linked with the early events initiated by allergen-mediated aggregation of IgE-occupied Fc RI. Fyn and Lyn initiate signaling events that are organized by adaptor molecules, which compartmentalize and coordinate the activity of activated protein and lipid kinases and phospholipases to generate lipid products essential for signal amplification and mast cell function. Fyn and Lyn counter-regulate phosphatidylinositol 3-OH kinase (PI3K), controlling the produced amount of phosphatidylinositol (3,4,5)-trisphosphate (PIP 3 ), a key regulator of mast cell degranulation. Fyn and Lyn also activate sphingosine kinases (SphK), which generate sphingosine-1-phosphate (S1P), thus contributing to mast cell chemotaxis and degranulation. Here, we summarize the current knowledge and future challenges and directions.