Ethanol Inhibits High-Affinity Immunoglobulin E Receptor (Fc epsilon RI) Signaling in Mast Cells by Suppressing the Function of Fc epsilon RI-Cholesterol Signalosome

0456170 - ÚMG 2016 RIV US eng J - Journal Article
Dráberová, Lubica - Paulenda, Tomáš - Hálová, Ivana - Potůčková, Lucie - Bugajev, Viktor - Bambousková, Monika - Tůmová, Magda - Dráber, Petr
Ethanol Inhibits High-Affinity Immunoglobulin E Receptor (Fc epsilon RI) Signaling in Mast Cells by Suppressing the Function of Fc epsilon RI-Cholesterol Signalosome.
PLoS ONE. Roč. 10, č. 12 (2015), e0144596-e0144596. ISSN 1932-6203. E-ISSN 1932-6203
R&D Projects: GA ČR(CZ) GBP302/12/G101; GA MŠMT LD12073
Institutional support: RVO:68378050
Keywords : KAPPA-B Activation * Lipid rafts * Nadph oxidase
Subject RIV: EB - Genetics ; Molecular Biology
Impact factor: 3.057, year: 2015

Ethanol has multiple effects on biochemical events in a variety of cell types, including the high-affinity immunoglobulin E receptor (Fc epsilon RI) signaling in antigen-activated mast cells. However, the underlying molecular mechanism remains unknown. To get better understanding of the effect of ethanol on Fc epsilon RI-mediated signaling we examined the effect of short-term treatment with non-toxic concentrations of ethanol on Fc epsilon RI signaling events in mouse bone marrow-derived mast cells. We found that 15 min exposure to ethanol inhibited antigen-induced degranulation, calcium mobilization, expression of proinflammatory cytokine genes (tumor necrosis factor-alpha, interleukin-6, and interleukin-13), and formation of reactive oxygen species in a dose-dependent manner. Removal of cellular cholesterol with methyl-beta-cyclodextrin had a similar effect and potentiated some of the inhibitory effects of ethanol. In contrast, exposure of the cells to cholesterol-saturated methyl-beta-cyclodextrin abolished in part the inhibitory effect of ethanol on calcium response and production of reactive oxygen species, supporting lipid-centric theories of ethanol action on the earliest stages of mast cell signaling. Further studies showed that exposure to ethanol and/or removal of cholesterol inhibited early Fc epsilon RI activation events, including tyrosine phosphorylation of the Fc epsilon RI beta and gamma subunits, SYK kinases, LAT adaptor protein, phospholipase C gamma, STAT5, and AKT and internalization of aggregated Fc epsilon RI. Interestingly, ethanol alone, and particularly in combination with methyl-beta-cyclodextrin, enhanced phosphorylation of negative regulatory tyrosine 507 of LYN kinase. Finally, we found that ethanol reduced passive cutaneous anaphylactic reaction in mice, suggesting that ethanol also inhibits Fc epsilon RI signaling under in vivo conditions.
Permanent Link: http://hdl.handle.net/11104/0256740