TGF-{beta} 1 Inhibits Mast Cell Fc {epsilon} RI Expression (original) (raw)
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Open Allergy …, 2009
Binding of monomeric Immunoglobulin E (IgE) to the high affinity IgE receptor (Fc RI) on mast cells induces a sensitization process which increases cell survival, augments membrane receptor expression and diminishes activation threshold. Although IgE-dependent sensitization is fundamental for allergic reactions, little is known about the influence of locally produced mediators on the outcome of a posterior allergen challenge. Since Transforming Growth Factor (TGF) is an important immunomodulator present in most of the tissues where mast cells reside, we decided to analyze the consequences of TGF exposure during the sensitization step of mast cells on a posterior IgE-antigen stimulation. Bone Marrow-derived Mast Cells (BMMCs) were sensitized with IgE in the presence or absence of TGF. Then, antigen was added and the secretion of the angiogenic cytokine Vascular Endothelial Growth Factor (VEGF) was determined. BMMCs sensitized with IgE+TGF showed an increased antigen-induced VEGF secretion compared to those sensitized with IgE alone. Sensitization with IgE+TGF did not modify membrane Fc RI receptor expression neither altered antigen-induced degranulation of the cells. Although both IgE and IgE+TGF sensitized cells showed an increase in VEGF mRNA stabilization after antigen addition, VEGF mRNA half-life was longer in IgE+TGF sensitized cells. p38 MAPK inhibitor SB202196 blocked VEGF mRNA stabilization after antigen addition specially on IgE+TGF sensitized cells. These findings suggest that TGF presence during the sensitization phase of mast cells can induce modifications to the Fc RI signal transduction system, provoking increased VEGF mRNA stabilization and protein secretion after IgE-antigen stimulation through a p38 MAPK-dependent mechanism.
TGF [Beta] 1 Induces Mast Cell Apoptosis
Experimental …, 2006
Mast cells are potent effectors of the inflammatory response, playing an important role in atopy, bacterial immunity, and animal models of arthritis, multiple sclerosis, and heart disease. Hence controlling mast cell numbers and responsiveness is essential for preventing inflammatory disease. We demonstrate that the cytokine transforming growth factor (TGF) β1 is a potent inducer of mast cell apoptosis, a finding that was consistent in cultured mouse bone marrowderived mast cells, peritoneal mast cells, and human mast cells. Cell death appeared to be caused by TGF-mediated repression of interleukin-3 (IL-3) receptor expression and function, leading to mitochondrial damage and activation of an apoptotic cascade acting via p53 and caspases. Although IL-3 receptor expression was reduced within 1 day of TGFβ1 stimulation, apoptosis required at least 3 days to occur. This delay in onset is postulated to allow protective mast cell effector functions, protecting the host from infection while preventing the establishment of chronic inflammation. Our data support the theory that TGFβ1 is an inhibitor of mast cell survival. The widespread expression of TGFβ1 offers this cytokine as an ideal candidate for control of mast cell homeostasis.
TGFβ1 induces mast cell apoptosis
Experimental Hematology, 2006
Mast cells are potent effectors of the inflammatory response, playing an important role in atopy, bacterial immunity, and animal models of arthritis, multiple sclerosis, and heart disease. Hence controlling mast cell numbers and responsiveness is essential for preventing inflammatory disease. We demonstrate that the cytokine transforming growth factor (TGF) b1 is a potent inducer of mast cell apoptosis, a finding that was consistent in cultured mouse bone marrow-derived mast cells, peritoneal mast cells, and human mast cells. Cell death appeared to be caused by TGF-mediated repression of interleukin-3 (IL-3) receptor expression and function, leading to mitochondrial damage and activation of an apoptotic cascade acting via p53 and caspases. Although IL-3 receptor expression was reduced within 1 day of TGFb1 stimulation, apoptosis required at least 3 days to occur. This delay in onset is postulated to allow protective mast cell effector functions, protecting the host from infection while preventing the establishment of chronic inflammation. Our data support the theory that TGFb1 is an inhibitor of mast cell survival. The widespread expression of TGFb1 offers this cytokine as an ideal candidate for control of mast cell homeostasis.
IL-4 and TGF- 1 Counterbalance One Another while Regulating Mast Cell Homeostasis
The Journal of Immunology, 2010
Mast cell responses can be altered by cytokines, including those secreted by Th2 and regulatory T cells (Treg). Given the important role of mast cells in Th2-mediated inflammation and recent demonstrations of Treg-mast cell interactions, we examined the ability of IL-4 and TGF-b1 to regulate mast cell homeostasis. Using in vitro and in vivo studies of mouse and human mast cells, we demonstrate that IL-4 suppresses TGF-b1 receptor expression and signaling, and vice versa. In vitro studies demonstrated that IL-4 and TGF-b1 had balancing effects on mast cell survival, migration, and Fc«RI expression, with each cytokine cancelling the effects of the other. However, in vivo analysis of peritoneal inflammation during Nippostrongylus brasiliensis infection in mice revealed a dominant suppressive function for TGF-b1. These data support the existence of a cytokine network involving the Th2 cytokine IL-4 and the Treg cytokine TGF-b1 that can regulate mast cell homeostasis. Dysregulation of this balance may impact allergic disease and be amenable to targeted therapy.
Genotype-Dependent Effects of TGF-β1 on Mast Cell Function: Targeting the Stat5 Pathway
We previously demonstrated that TGF-β1 suppresses IgE-mediated signaling in human and mouse mast cells in vitro, an effect that correlated with decreased expression of the high-affinity IgE receptor, FcεRI. The in vivo effects of TGF-β1 and the means by which it suppresses mast cells have been less clear. This study shows that TGF-β1 suppresses FcεRI and c-Kit expression in vivo. By examining changes in cytokine production concurrent with FcεRI expression, we found that TGF-β1 suppresses TNF production independent of FcεRI levels. Rather, IgE-mediated signaling was altered. TGF-β1 significantly reduced expression of Fyn and Stat5, proteins critical for cytokine induction. These changes may partly explain the effects of TGF-β1, because Stat5B overexpression blocked TGF-mediated suppression of IgE-induced cytokine production. We also found that Stat5B is required for mast cell migration toward stem cell factor, and that TGF-β1 reduced this migration. We found evidence that genetic bac...
High-affinity IgE receptor-β chain expression in human mast cells
Journal of Immunological Methods, 2008
The high-affinity IgE receptor (FcεRI)-β gene is one of the atopy-associated genes, but its biological significance is largely unknown. In this study, we generated the anti-FcεRI-β chain antibody to clarify β-chain protein expression in human mast cells. The FcεRI-β antibody showed specific binding to a 27 kDa protein with Western blotting and membrane bound immunostaining using cultured mast cells. Monomeric IgE sensitization increased β-chain expression as well as mature α-chain expression in mast cells. Upregulation of β-chain expression with monomeric IgE treatment suggests possible roles of FcεRI-β protein as an atopy-related molecule.