| dc.description | The mechanisms of allergic disease development and progression are not well understood. Although IgE mediated activation of mast cells is one of the main features of allergy, recent evidence suggests that host-pathogen interactions also contribute to the initiation and severity of disease. Infection with a number of pathogens is associated with exacerbation of allergic diseases including asthma, suggesting that pathogen products can induce the production of bronchoactive mediators such as leukotriene (LT) C4. However, the mechanisms of such mediator production are unclear. We hypothesized that human mast cells could produce LTC4 in response to pathogen products such as zymosan, a yeast cell wall component, and peptidoglycan from the cell walls of Gram positive bacteria. Both of these products activate Toll-like receptor 2, however, zymosan has also been shown to utilize a co-receptor molecule known as dectin-1 in other cell types. Both peptidoglycan and zymosan-induced significant amounts of LTB4 and LTC4 from human cord blood derived mast cells (CBMC), without concurrent degranulation. CBMC as well as the mast cell line KU-812 expressed a functional isoform of dectin-1. The dectin-1 inhibitors laminarin and glucan phosphate as well as inhibitors of Syk tyrosine kinase activity significantly reduced the LTC4 response to zymosan but not to peptidoglycan. In contrast, dectin-1 blockade did not significantly inhibit the mast cell IL-1beta or GM-CSF responses to either of these activators. Antibody blockade of Toll-like receptor 2 function significantly decreased zymosan-induced LTC4 production by human mast cells. Increased phosphorylation of the MAP kinase p38 was observed in response to zymosan or PGN treatment and functional inhibition of p38 decreased zymosan-induced LTC4 production was investigated. Inhibition of MAP kinase function did not affect GM-CSF production in response to zymosan treatment. Inhibition of phosphatidylinositol-1,4,5-kinase (PI3K) dose-dependently decreased zymosan and PGN-induced LTC4 production. These data demonstrate a novel role for dectin-1, TLR2 and PI3K in the selective, degranulation-independent generation of leukotrienes from human mast cells and suggest new approaches to the selective modulation of lipid mediator production in disease. | en_US |
