The 1,4-benzodiazepine Ro5-4864 (4-chlorodiazepam) suppresses multiple pro-inflammatory mast cell effector functions

Cell Communication and Signaling

Research

Bernd Hildenbrand¹  Felix Kratz²  Gerhard J Molderings³  Christian Martin⁴  Michael Huber⁵  Omid Sascha Yousefi⁵  Marcel Kuhny⁵  Karin Maschke-Neuß⁵  Thomas Wilhelm⁵ 

[1] Department of Clinical Research, Tumor Biology Center, Breisacher Str. 117, 79106, Freiburg, Germany;Division of Macromolecular Prodrugs, Tumor Biology Center, Breisacher Str. 117, 79106, Freiburg, Germany;Institute of Human Genetics, University Hospital of Bonn, Sigmund-Freud-Str. 25, 53127, Bonn, Germany;Medical Faculty, Department of Pharmacology and Toxicology, RWTH Aachen University, Wendlingweg 2, 52074, Aachen, Germany;Medical Faculty, Institute of Biochemistry and Molecular Immunology, RWTH Aachen University, Pauwelsstr. 30, 52074, Aachen, Germany;

关键词: Mast cell;    Benzodiazepines;    Lyn;    SHIP1;    Mastocytosis;    Inflammation;    Allergy;   

DOI  :  10.1186/1478-811X-11-13

 received in 2012-09-10, accepted in 2013-02-16,  发布年份 2013

来源: Springer

【 摘 要 】

Activation of mast cells (MCs) can be achieved by the high-affinity receptor for IgE (FcεRI) as well as by additional receptors such as the lipopolysaccharide (LPS) receptor and the receptor tyrosine kinase Kit (stem cell factor [SCF] receptor). Thus, pharmacological interventions which stabilize MCs in response to different receptors would be preferable in diseases with pathological systemic MC activation such as systemic mastocytosis. 1,4-Benzodiazepines (BDZs) have been reported to suppress MC effector functions. In the present study, our aim was to analyze molecularly the effects of BDZs on MC activation by comparison of the effects of the two BDZs Ro5-4864 and clonazepam, which markedly differ in their affinities for the archetypical BDZ recognition sites, i.e., the GABAA receptor and TSPO (previously termed peripheral-type BDZ receptor). Ro5-4864 is a selective agonist at TSPO, whereas clonazepam is a selective agonist at the GABAA receptor. Ro5-4864 suppressed pro-inflammatory MC effector functions in response to antigen (Ag) (degranulation/cytokine production) and LPS and SCF (cytokine production), whereas clonazepam was inactive. Signaling pathway analyses revealed inhibitory effects of Ro5-4864 on Ag-triggered production of reactive oxygen species, calcium mobilization and activation of different downstream kinases. The initial activation of Src family kinases was attenuated by Ro5-4864 offering a molecular explanation for the observed impacts on various downstream signaling elements. In conclusion, BDZs structurally related to Ro5-4864 might serve as multifunctional MC stabilizers without the sedative effect of GABAA receptor-interacting BDZs.

【 授权许可】

Unknown   
© Yousefi et al; licensee BioMed Central Ltd. 2013. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.