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Activation of mast cells by incorporation of cholesterol into rafts

Activation of mast cells by incorporation of cholesterol into rafts IgE plus antigen‐stimulated mast cells degranulate, synthesize leukotrienes and secrete cytokines. According to the coalescence model this process is initiated in specific membrane compartments termed rafts. There, enhanced levels of glycosphingolipids and cholesterol stabilize the interaction of FcϵRI and Lyn, and thus facilitate the first steps of signal transduction. Enforced changes in raft architecture by cholesterol deprivation and exogenous application of glycosphingolipids influence these early events by loss of tyrosine kinase activity or receptor‐independent signal initiation respectively. Here we show that exogenously added cholesterol accumulates in rafts and activates mast cells. An investigation of the signaling events reveals that in contrast to IgE plus antigen‐mediated stimulation, cholesterol triggers p38 mitogen‐activated protein kinase and preferentially induces expression of FosB. Consequently, a comparative large‐scale microarray analysis demonstrates that a number of IgE plus antigen‐induced immediate early genes (peak expression at 30 min after induction) are repressed by cholesterol. These changes further translate into altered expression levels and time kinetics of a number of early genes (peak expression at 2 h after stimulation). As the most prominent example for cholesterol‐dependent genes, we identified PAI1 (plasminogen activator inhibitor 1), a protein regarded as a risk factor for atherosclerosis. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png International Immunology Oxford University Press

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References (35)

Publisher
Oxford University Press
Copyright
The Japanese Society for Immunology
ISSN
0953-8178
eISSN
1460-2377
DOI
10.1093/intimm/dxg120
Publisher site
See Article on Publisher Site

Abstract

IgE plus antigen‐stimulated mast cells degranulate, synthesize leukotrienes and secrete cytokines. According to the coalescence model this process is initiated in specific membrane compartments termed rafts. There, enhanced levels of glycosphingolipids and cholesterol stabilize the interaction of FcϵRI and Lyn, and thus facilitate the first steps of signal transduction. Enforced changes in raft architecture by cholesterol deprivation and exogenous application of glycosphingolipids influence these early events by loss of tyrosine kinase activity or receptor‐independent signal initiation respectively. Here we show that exogenously added cholesterol accumulates in rafts and activates mast cells. An investigation of the signaling events reveals that in contrast to IgE plus antigen‐mediated stimulation, cholesterol triggers p38 mitogen‐activated protein kinase and preferentially induces expression of FosB. Consequently, a comparative large‐scale microarray analysis demonstrates that a number of IgE plus antigen‐induced immediate early genes (peak expression at 30 min after induction) are repressed by cholesterol. These changes further translate into altered expression levels and time kinetics of a number of early genes (peak expression at 2 h after stimulation). As the most prominent example for cholesterol‐dependent genes, we identified PAI1 (plasminogen activator inhibitor 1), a protein regarded as a risk factor for atherosclerosis.

Journal

International ImmunologyOxford University Press

Published: Oct 1, 2003

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