Essential role of the prosurvival bcl-2 homologue A1 in mast cell survival after allergic activation.
Mast cells reside in tissues, where upon activation through the high-affinity-IgE-receptor (FcepsilonRI) they degranulate and orchestrate the allergic reaction. Mast cells survive this activation and can thus be reactivated. In this study we demonstrate that this process depends on the pro-survival gene A1. Activation of mast cells through FcepsilonRI resulted in degranulation, strong induction of A1 mRNA and protein, and cell survival. In contrast, A1-deficient mast cells released granule mediators similar to the wild-type control, but the cells did not survive an allergic activation. Furthermore, A1(-/-) mice that had been sensitized and provoked with allergen exhibited a lower number of mast cell compared with littermate controls. The induction of A1 was dependent on calcium, as EDTA prevented A1 expression. The calcium ionophore, ionomycin, induced A1 expression and mast cell survival, whereas compound 48/80, a well-known mast cell secretagogue, did not. This study uncovers the importance of A1 for mast cell survival in allergic reactions, and it proposes A1 as a potential target for the treatment of allergic diseases.
Xiang
Z
Z
Research Group on Mast Cell Biology, Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, 751 85 Uppsala, Sweden.
Ahmed
A A
AA
Möller
C
C
Nakayama
K
K
Hatakeyama
S
S
Nilsson
G
G
D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D002460:Cell Line; D002470:Cell Survival; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006967:Hypersensitivity / Q000276:immunology*; D007377:Interleukin-3 / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D015759:Ionomycin / Q000494:pharmacology; D008407:Mast Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020932:Nerve Growth Factor / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000276:immunology*; D017455:Receptors, IgE / Q000276:immunology; D051818:Replication Protein C; D019089:Stem Cell Factor / Q000494:pharmacology; D015854:Up-Regulation; D003189:p-Methoxy-N-methylphenethylamine / Q000494:pharmacology
D004268:DNA-Binding Proteins; D007377:Interleukin-3; D019253:Proto-Oncogene Proteins c-bcl-2; D017455:Receptors, IgE; D019089:Stem Cell Factor; D015847:Interleukin-4; D003189:p-Methoxy-N-methylphenethylamine; D015759:Ionomycin; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D020932:Nerve Growth Factor; D051818:Replication Protein C