The 1,4-benzodiazepine Ro5-4864 (4-chlorodiazepam) suppresses multiple pro-inflammatory mast cell effector functions
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- 作者：Omid Sascha Yousefi (1)
Thomas Wilhelm (1)
Karin Maschke-Neu? (1)
Marcel Kuhny (1)
Christian Martin (2)
Gerhard J Molderings (3)
Felix Kratz (4)
Bernd Hildenbrand (5)
Michael Huber (1) - 关键词：Mast cell ; Benzodiazepines ; Lyn ; SHIP1 ; Mastocytosis ; Inflammation ; Allergy
- 刊名：Cell Communication and Signaling
- 出版年：2013
- 出版时间：December 2013
- 年：2013
- 卷：11
- 期：1
- 全文大小：852KB
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Thomas Wilhelm (1)
Karin Maschke-Neu? (1)
Marcel Kuhny (1)
Christian Martin (2)
Gerhard J Molderings (3)
Felix Kratz (4)
Bernd Hildenbrand (5)
Michael Huber (1)
1. Medical Faculty, Institute of Biochemistry and Molecular Immunology, RWTH Aachen University, Pauwelsstr. 30, 52074, Aachen, Germany
2. Medical Faculty, Department of Pharmacology and Toxicology, RWTH Aachen University, Wendlingweg 2, 52074, Aachen, Germany
3. Institute of Human Genetics, University Hospital of Bonn, Sigmund-Freud-Str. 25, 53127, Bonn, Germany
4. Division of Macromolecular Prodrugs, Tumor Biology Center, Breisacher Str. 117, 79106, Freiburg, Germany
5. Department of Clinical Research, Tumor Biology Center, Breisacher Str. 117, 79106, Freiburg, Germany
文摘
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.