Stem cell factor promotes mast cell survival via inactivation of FOXO3a-mediated transcriptional induction and MEK-regulated phosphorylation of the proapoptotic protein Bim

Abstract

Mast cells are found in tissues throughout the body where they play important roles in the regulation of inflammatory responses. One characteristic feature of mast cells is their longevity. Although it is well established that mast cell survival is dependent on stem cell factor (SCF), it has not been described how this process is regulated. Herein, we report that SCF promotes mast cell survival through inactivation of the Forkhead transcription factor FOXO3a (forkhead box, class O3A) and down-regulation and phosphorylation of its target Bim (Bcl- 2 IntroductionMast cells are long-lived multifunctional effector cells of the immune system originating from the hematopoietic CD34 ϩ stem cells found in the bone marrow. 1 From the bone marrow, mast cell precursors enter the circulation where they are recruited into peripheral tissues to mature and express their final phenotype under the influence of stem cell factor (SCF) and other locally produced cytokines. 2 Although best known for their role in allergic reactions, mast cells are now also recognized as cells of importance in both innate immunity and in the onset and severity of chronic inflammations. 3,4 The versatile effector mechanisms mast cells have been endowed with can be deduced from their capability to release a wide variety of inflammatory mediators such as histamine, proteases, and cytokines that are preformed and stored in granules and prostaglandins, leukotrienes, and cytokines that are secreted upon activation. 5 The number of tissue mast cells is normally relatively constant, but during an acute or chronic inflammation the number can increase substantially. 6 The regulation of mast cell numbers is most likely regulated by proliferation, migration, and apoptosis or survival. The mechanisms that regulate the viability of mature mast cells or promote mast cell apoptosis are poorly investigated. SCF is a cardinal growth factor in mast cell biology, regulating mast cell growth, differentiation, adhesion, migration, and survival. 7 The number of tissue mast cells is at least in part regulated by SCF produced by resident stromal cells. SCF rescues mast cells from spontaneous apoptosis in vitro, whereas inhibition of SCF synthesis in vivo leads to mast cell apoptosis. [8][9][10] Although it is accepted that SCF is a prosurvival factor for mast cells, it remains largely unclear how SCF promotes survival in these cells.The B-cell lymphoma-2 (Bcl-2) family, which contains both prosurvival and proapoptotic proteins, are essential regulators of cell survival and apoptosis. 11 The levels and interactions of prosurvival versus proapoptotic Bcl-2 family proteins determine whether a cell survives or will undergo apoptosis. During apoptosis induced by proapoptotic Bcl-2 family members, cytochrome c is released from the mitochondria and a caspase cascade is activated that induces DNA fragmentation. 12,13 The prosurvival Bcl-2 family members include Bcl-2, Bcl-X L , Bcl-w, Mcl-1 (myeloid cell For personal use only. on May 12, 2018. by guest www.bloodjournal.org From leuk...

Foxo‐mediated Bim transcription is dispensable for the apoptosis of hematopoietic cells that is mediated by this BH3‐only protein

“…As reported [20], mast cells from Bim À / À and Foxo3a À / À mice survived cytokine deprivation significantly better than wt cells, whereas the Bim DFoxo/DFoxo mast cells died at a normal rate (Fig 5D). Cytokine deprivation caused comparable levels of Bim protein upregulation in wt, Foxo3a À / À and Bim DFoxo/DFoxo mast cells (Fig 5E).…”

Follicle-stimulating Hormone Regulates Pro-apoptotic Protein Bcl-2-interacting Mediator of Cell Death-Extra Long (BimEL)-induced Porcine Granulosa Cell Apoptosis

“…This finding is in agreement with the results of several previous studies in which changes in the electrophoretic mobility of Bim EL were attributed to phosphorylation and dephosphorylation. Möller et al (47) showed that a stem cell factor-induced band shift of Bim EL in mouse mast cells was due to phosphorylation and indicated that the larger band represented phosphorylated Bim EL after treatment with alkaline phosphatase. Abayasiriwardana et al (48) also reported that this shift was abolished by alkaline phosphatase-mediated dephosphorylation but was restored if the phosphatase was inhibited by sodium orthovanadate in malignant mesothelioma cells.…”

Is there a role for mast cells in psoriasis?

“…The stem cell factor (SCF) (Kit ligand) is a well-known and essential factor for the growth, migration, activation and survival of human mast cells developed and cultured in vitro [93,123,133,134] or isolated from skin specimens [45,85]. SCF injected subcutaneously induces anaphylactic-like activation and degranulation of dermal mast cells in situ followed by inXammatory cell recruitment such as neutrophils, eosinophils and basophils [35].…”