Regulation of mast cell survival and apoptosis

Mature mast cells reside in the tissue as heavily granulated cells possessing a regulatory function in innate and adaptive immunity against pathogens, but also detrimentally in atopic, as well as, chronic inflammation-associated diseases such as allergic reactions and autoimmunity. Upon stimulation, mast cells release a vast variety of mediators that recruit and stimulate other immune cells, induce vasodilation and angiogenesis, and process and degrade proteins. Mast cells are long-lived cells and can survive the harsh process of degranulation followed upon IgE receptor activation. In human mast cells, IgE receptor activation induces increased expression of the anti-apoptotic protein Bfl-1/A1, which has been demonstrated crucial for activation-induced survival in mouse. Upon stimulation with the TH1 cytokine, IFNgamma mast cells upregulate the normally not expressed high affinity receptor for IgG. Here we show that IFNgamma stimulated human mast cells, activated via IgG receptor crosslinking, are rescued from cytokine deprivation-induced apoptosis and express increased levels of Bfl-1. In mouse, the activation-induced mast cell survival has been correlated to the upregulation of A1. This anti-apoptotic protein is described to be under transcriptional control of the nuclear factor-kappaB (NF-kappaB), and being expressed upon activation in several cell types such as T- and B-lymphocytes. However, by using mast cells from NF-kappaB deficient mice, stable transfections of IkappaB-alpha super repressor, and promoter gene analysis with deleted NF-kappaB binding sites, we here demonstrate that NF-kappaB is not involved in activation-induced upregulation of A1 in mast cells. Instead, our data from using the calcineurin inhibitor, cyclosporin A, electrophoretic mobility shift assay and chromatin immunoprecipitation suggest NFAT to be the important regulator of A1 transcription. Bfl-1/A1 is a member of the Bcl-2 protein family, which control the intrinsic pathway of apoptosis. Interactions between pro- and anti-apoptotic ...