No abstract

Kit regulation of mast cell proliferation and differentiation has been intimately linked to the activation of phosphatidylinositol 3-OH kinase (PI3K). The activating D816V mutation of Kit, seen in the majority of mastocytosis patients, causes a robust activation of PI3K signals. However, whether increased PI3K signaling in mast cells is a key element for their in vivo hyperplasia remains unknown. Here we report that dysregulation of PI3K signaling in mice by deletion of the phosphatase and tensin homolog (Pten) gene (which regulates the levels of the PI3K product, phosphatidylinositol 3,4,5-trisphosphate) caused mast cell hyperplasia and increased numbers in various organs. Selective deletion of Pten in the mast cell compartment revealed that the hyperplasia was intrinsic to the mast cell. Enhanced STAT5 phosphorylation and increased expression of survival factors, such as Bcl-XL, were observed in PTENdeficient mast cells, and these were further enhanced by stem cell factor stimulation. Mice carrying PTEN-deficient mast cells also showed increased hypersensitivity as well as increased vascular permeability. Thus, Pten deletion in the mast cell compartment results in a mast cell proliferative phenotype in mice, demonstrating that dysregulation of PI3K signals is vital to the observed mast cell hyperplasia.(Blood. 2011;118(20): 5466-5475) IntroductionMast cells (MCs) are innate immune cells that also serve to amplify adaptive immunity. 1 They are best known for their role as effector cells in allergic disease, 2 but there is considerable evidence of a beneficial role for these cells in host defense and immune regulation. 3 In various pathologic circumstances, MC numbers can be increased because of hyperplasia or neoplastic transformation. 4,5 Mastocytosis is a term used to collectively describe MC hyperplasia/ neoplasia in one or more organs. Systemic mastocytosis normally involves one or more visceral organs with or without skin involvement. The majority of patients with mastocytosis carry a somatic mutation in the Kit proto-oncogene, the receptor for SCF that is central to MC proliferation and differentiation. Substitution of D for V at position 816 in the kinase domain of the receptor results in constitutive (SCF-independent) activation of Kit and enhanced MC proliferation. 6 It is well known that signals generated by SCF engagement of Kit are highly dependent on the activity of phosphatidylinositol 3-OH kinase (PI3K). [7][8][9][10] In addition, PI3K activity is also increased by the D816V mutation of Kit. 9 Proliferation of murine MCs is also partly dependent on IL-3 and its receptor (IL-3R). 11,12 Human intestinal MCs also express functional IL-3R, and IL-3 stimulation causes enhanced growth rates and effector responses. 13 Interestingly, IL-3R activity and its role in regulating proliferative responses are also tightly coupled to the activation of PI3K. 14 In addition, STAT5 is also important to the transcriptional activity induced by the IL-3R and c-Kit, and STAT5-PI3K-Akt signals are known to be essenti...