Stimulus strength determines the BTK-dependence of the SHIP1-deficient phenotype in IgE/antigen-triggered mast cells

Autor:	Anne Simonowski, Carolin N. Zorn, Michael Huber
Jazyk:	angličtina
Rok vydání:	2018
Předmět:	0301 basic medicine medicine.medical_treatment lcsh:Medicine Bone Marrow Cells Immunoglobulin E Article Cell Degranulation Proinflammatory cytokine Diglycerides Mice Phosphatidylinositol 3-Kinases 03 medical and health sciences 0302 clinical medicine hemic and lymphatic diseases Agammaglobulinaemia Tyrosine Kinase medicine Animals Bruton's tyrosine kinase Mast Cells Antigens Phosphorylation Extracellular Signal-Regulated MAP Kinases lcsh:Science Multidisciplinary biology Phospholipase C gamma Receptors IgE Chemistry Effector lcsh:R Degranulation Cell biology Enzyme Activation Phenotype 030104 developmental biology Cytokine Phosphatidylinositol-3 4 5-Trisphosphate 5-Phosphatases 030220 oncology & carcinogenesis biology.protein Cytokines Calcium lcsh:Q Signal transduction Tyrosine kinase Signal Transduction
Zdroj:	Scientific Reports, Vol 8, Iss 1, Pp 1-13 (2018) Scientific reports 8, 15467 (2018). doi:10.1038/s41598-018-33769-1 Scientific Reports
ISSN:	2045-2322
DOI:	10.1038/s41598-018-33769-1
Popis:	Antigen (Ag)-mediated crosslinking of IgE-loaded high-affinity receptors for IgE (FcεRI) on mast cells (MCs) triggers activation of proinflammatory effector functions relevant for IgE-associated allergic disorders. The cytosolic tyrosine kinase BTK and the SH2-containing inositol-5′-phosphatase SHIP1 are central positive and negative regulators of Ag-triggered MC activation, respectively, contrarily controlling Ca2+ mobilisation, degranulation, and cytokine production. Using genetic and pharmacological techniques, we examined whether BTK activation in Ship1−/− MCs is mandatory for the manifestation of the well-known hyperactive phenotype of Ship1−/− MCs. We demonstrate the prominence of BTK for the Ship1−/− phenotype in a manner strictly dependent on the strength of the initial Ag stimulus; particular importance for BTK was identified in Ship1−/− bone marrow-derived MCs in response to stimulation with suboptimal Ag concentrations. With respect to MAPK activation, BTK showed particular importance at suboptimal Ag concentrations, allowing for an analogous-to-digital switch resulting in full activation of ERK1/2 already at low Ag concentrations. Our data allow for a more precise definition of the role of BTK in FcεRI-mediated signal transduction and effector function in MCs. Moreover, they suggest that reduced activation or curtate expression of SHIP1 can be compensated by pharmacological inhibition of BTK and vice versa.
Databáze:	OpenAIRE
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