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International Immunology, Vol. 15, No. 10, pp. 1207-1218, October 2003
© 2003 Japanese Society for Immunology

Activation of mast cells by incorporation of cholesterol into rafts

Thomas Baumruker1, Robert Csonga1, Edith Pursch1, Andrea Pfeffer1, Nicole Urtz1, Sue Sutton2, Elisa Bofill-Cardona1, Michael Cooke2 and Eva Prieschl1

1 Novartis Research Institute, Brunner Strasse 59, 1235 Vienna, Austria 2 Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121, USA

Correspondence to: T. Baumruker; E-mail: thomas.baumruker{at}pharma.novartis.com
Transmitting editor: S. J. Galli

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 Fc{epsilon}RI 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.

Keywords: basophil, gene regulation, lipid mediator, mast cell, signal transduction, transcription factor


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