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Activation of KIT modulates the function of tumor necrosis factor‐related apoptosis‐inducing ligand receptor (TRAIL‐R) in mast cells
Author(s) -
Förster A.,
Grotha S. P.,
Seeger J. M.,
Rabenhorst A.,
Gehring M.,
Raap U.,
Létard S.,
Dubreuil P.,
Kashkar H.,
Walczak H.,
Roers A.,
Hartmann K.
Publication year - 2015
Publication title -
allergy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.363
H-Index - 173
eISSN - 1398-9995
pISSN - 0105-4538
DOI - 10.1111/all.12612
Subject(s) - apoptosis , tumor necrosis factor alpha , receptor , tumor necrosis factor receptor , immunology , cancer research , function (biology) , microbiology and biotechnology , medicine , chemistry , biology , biochemistry
Background Mastocytosis is characterized by the accumulation of mast cells ( MC s) associated with activating mutations of KIT . Tumor necrosis factor‐related apoptosis‐inducing ligand receptors ( TRAIL ‐Rs) are preferentially expressed on neoplastic cells and induce the extrinsic apoptotic pathway. Recent studies reported on the expression of TRAIL ‐Rs and TRAIL ‐induced apoptosis in cultured human MC s, which depend on stem cell factor ( SCF )‐induced or constitutive KIT activation. Material and methods We sought to further define the impact of TRAIL ‐Rs on MC s in vivo and in vitro . Using Cre/loxP recombination, we generated mice with MC ‐specific and ubiquitous knockout of TRAIL ‐R. In these mice, anaphylaxis and numbers of MC s were investigated. We also explored the expression and function of TRAIL ‐Rs in cultured murine and human MC s upon activation of KIT . By conducting immunofluorescence staining, we analyzed the expression of TRAIL ‐Rs in MC s infiltrating the bone marrow of patients with mastocytosis. Results MC ‐specific deletion of TRAIL ‐R was associated with a slight, but significant increase in anaphylaxis. Numbers of MC s in MC ‐specific knockouts of TRAIL ‐R were comparable to controls. Whereas cultured IL ‐3‐dependent murine MC s from wild‐type mice were resistant to TRAIL ‐induced apoptosis, SCF ‐stimulated MC s underwent apoptosis in response to TRAIL . Interestingly, activating KIT mutations also promoted sensitivity to TRAIL ‐mediated apoptosis in human MC s. In line with these findings, MC s infiltrating the bone marrow of patients with mastocytosis expressed TRAIL ‐R1. Conclusions Activation of KIT regulates the function of TRAIL ‐Rs in MC s. TRAIL ‐R1 may represent an attractive diagnostic and therapeutic target in diseases associated with KIT mutations, such as mastocytosis.

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