Foerster, A., Grotha, S. P., Seeger, J. M., Rabenhorst, A., Gehring, M., Raap, U., Letard, S., Dubreuil, P., Kashkar, H., Walczak, H., Roers, A. and Hartmann, K. (2015). Activation of KIT modulates the function of tumor necrosis factor-related apoptosis-inducing ligand receptor (TRAIL-R) in mast cells. Allergy, 70 (7). S. 764 - 775. HOBOKEN: WILEY. ISSN 1398-9995

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Abstract

BackgroundMastocytosis is characterized by the accumulation of mast cells (MCs) 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 MCs, which depend on stem cell factor (SCF)-induced or constitutive KIT activation. Material and methodsWe sought to further define the impact of TRAIL-Rs on MCs 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 MCs were investigated. We also explored the expression and function of TRAIL-Rs in cultured murine and human MCs upon activation of KIT. By conducting immunofluorescence staining, we analyzed the expression of TRAIL-Rs in MCs infiltrating the bone marrow of patients with mastocytosis. ResultsMC-specific deletion of TRAIL-R was associated with a slight, but significant increase in anaphylaxis. Numbers of MCs in MC-specific knockouts of TRAIL-R were comparable to controls. Whereas cultured IL-3-dependent murine MCs from wild-type mice were resistant to TRAIL-induced apoptosis, SCF-stimulated MCs underwent apoptosis in response to TRAIL. Interestingly, activating KIT mutations also promoted sensitivity to TRAIL-mediated apoptosis in human MCs. In line with these findings, MCs infiltrating the bone marrow of patients with mastocytosis expressed TRAIL-R1. ConclusionsActivation of KIT regulates the function of TRAIL-Rs in MCs. TRAIL-R1 may represent an attractive diagnostic and therapeutic target in diseases associated with KIT mutations, such as mastocytosis.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Foerster, A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Grotha, S. P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Seeger, J. M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rabenhorst, A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gehring, M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Raap, U.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Letard, S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dubreuil, P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kashkar, H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Walczak, H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Roers, A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hartmann, K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-399831
DOI: 10.1111/all.12612
Journal or Publication Title: Allergy
Volume: 70
Number: 7
Page Range: S. 764 - 775
Date: 2015
Publisher: WILEY
Place of Publication: HOBOKEN
ISSN: 1398-9995
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
MASTOCYTOSIS; DIFFERENTIATION; GROWTH; IGEMultiple languages
Allergy; ImmunologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/39983

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