Why Is It So Hard to Kill a Mast Cell?A Study of Mast Cell Activation and Survival

Sammanfattning: Mast cells have a long life in tissues, where they are involved in inflammatory and hypersensitivity reactions. Activation through cross-linking of the high-affinity IgE-receptor (FcεRI) is a primary stimulus capable of degranulating mast cells, contributing to symptoms of allergy. The aim of this study was to investigate the mechanisms by which mast cells survive the allergic activation. The study confirmed on a continual single-cell basis that mast cells could indeed recover from the IgE-mediated degranulation and be activated again. For the second activation, kinetics of synthesis and release of certain mediators paralleled those of the initial activation. Mast cell survival was promoted due to a decreased level of apoptosis as a result of activation by FcεRI, suggesting that the activation initiated an anti-apoptotic program in mast cells. Given the potential survival- promoting role of nerve growth factor (NGF) in many cell types, we determined whether mast cells released and responded to NGF. It was found that mast cells expressed functional TrkA, the high-affinity receptor for NGF. Furthermore, the release of NGF was increased from degranulating mast cells in response to FcεRI cross-linking. Next, the possible effects of anti-apoptotic Bcl-2 family genes on mast cell survival were examined. Following FcεRI aggregation, transcripts of the pro-survival Bcl-2 homologue Al were remarkably up-regulated in mast cells. In contrast, degranulating mast cells from Al knock-out mice failed to exhibit survival advantage. These data strongly suggest that Al is required for mast call survival following allergic activation. In conclusion, stimuli causing an allergic reaction trigger mast cells to release NGF and up- regulate Al, which may contribute to the survival of mast cells. Our finding may be of significance in understanding the mechanisms underlying the long life-span of mast cells during allergic reactions and hence indicate possible therapeutic interventions.