Mast cells play a pivotal role in the pathogenesis of asthma and other allergic diseases. These reactions are generally initiated by antigen-dependent aggregation of the high affinity IgE receptor (Fc-epsilon-RI) expressed on the cell surface and subsequent release of pro-inflammatory mediators (e.g. histamine, prostanoids, proteases and cytokines). We have demonstrated that interferon-gamma up-regulates the high affinity receptor for IgG (Fc-gamma-RI) on cultured human mast cells and that aggregation of these receptors leads to mast cell mediator release. An objectof this study is to delineate the signaling pathways of Fc-epsilon-RI and Fc-gamma-RI receptors leading to the release of inflammatory mediators from human mast cells. The current model for the signaling pathway linking Fc-epsilon-RI to mast cell activation has largely been based on studies conducted in RBL 2H3 cells. RBL 2H3 cells are a transformed rodent cell line, which may not be, in all aspects, reflective of the mature human mast cells. The signaling pathways linking the Fc-gamma-RI receptor to mast cell activation have yet to be delineated. It is now possible to grow human mast cells from a CD34-positive, pluripotent cell population in primary culture with sufficient number and purity to study defined signaling events. Thus, we are now examining specific signaling pathways involved in Fc-epsilon-RI- and Fc-gamma-RI- dependent inflammatory mediator release from human mast cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Intramural Research (Z01)
Project #
1Z01AI000850-02
Application #
6431716
Study Section
(LAD)
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2000
Total Cost
Indirect Cost
Name
Niaid Extramural Activities
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Olivera, Ana; Urtz, Nicole; Mizugishi, Kiyomi et al. (2006) IgE-dependent activation of sphingosine kinases 1 and 2 and secretion of sphingosine 1-phosphate requires Fyn kinase and contributes to mast cell responses. J Biol Chem 281:2515-25
Furumoto, Yasuko; Brooks, Steve; Olivera, Ana et al. (2006) Cutting Edge: Lentiviral short hairpin RNA silencing of PTEN in human mast cells reveals constitutive signals that promote cytokine secretion and cell survival. J Immunol 176:5167-71
Rivera, Juan; Gilfillan, Alasdair M (2006) Molecular regulation of mast cell activation. J Allergy Clin Immunol 117:1214-25; quiz 1226
Fattakhova, Gul'nar; Masilamani, Madhan; Borrego, Francisco et al. (2006) The high-affinity immunoglobulin-E receptor (FcepsilonRI) is endocytosed by an AP-2/clathrin-independent, dynamin-dependent mechanism. Traffic 7:673-85
Gilfillan, Alasdair M; Tkaczyk, Christine (2006) Integrated signalling pathways for mast-cell activation. Nat Rev Immunol 6:218-30
Yamaoka, Kunihiro; Min, Booki; Zhou, Yong-Jie et al. (2005) Jak3 negatively regulates dendritic-cell cytokine production and survival. Blood 106:3227-33
Iwaki, Shoko; Tkaczyk, Christine; Satterthwaite, Anne B et al. (2005) Btk plays a crucial role in the amplification of Fc epsilonRI-mediated mast cell activation by kit. J Biol Chem 280:40261-70
Hundley, Thomas R; Gilfillan, Alasdair M; Tkaczyk, Christine et al. (2004) Kit and FcepsilonRI mediate unique and convergent signals for release of inflammatory mediators from human mast cells. Blood 104:2410-7
Tkaczyk, Christine; Okayama, Yoshimichi; Metcalfe, Dean D et al. (2004) Fcgamma receptors on mast cells: activatory and inhibitory regulation of mediator release. Int Arch Allergy Immunol 133:305-15
Ali, Khaled; Bilancio, Antonio; Thomas, Matthew et al. (2004) Essential role for the p110delta phosphoinositide 3-kinase in the allergic response. Nature 431:1007-11

Showing the most recent 10 out of 21 publications