Abstract

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 also 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 through IgG leads to mast cell mediator release. Our studies are directed at delineating the signaling pathways initiated by Fc-epsilon-RI and Fc-gamma-RI receptors. The signaling pathways linking the Fc aggregation to human 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 have been examining specific signaling pathways involved in Fc-epsilon-RI- and Fc-gamma-RI- dependent inflammatory mediator release from human mast cells. The goal is to identify new therapeutic targets in the treatment of allergic diseases.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Intramural Research (Z01)
Project #
1Z01AI000850-04
Application #
6669760
Study Section
(LAD)
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2002
Total Cost
Indirect Cost

  Institution

Name
Niaid Extramural Activities
Department
Type
DUNS #
City
State
Country
United States
Zip Code

  Publications

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
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
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
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
Tkaczyk, Christine; Horejsi, Vaclav; Iwaki, Shoko et al. (2004) NTAL phosphorylation is a pivotal link between the signaling cascades leading to human mast cell degranulation following Kit activation and Fc epsilon RI aggregation. Blood 104:207-14
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

Showing the most recent 10 out of 21 publications