Ethanol induces the production of cytokines via the Ca2+ MAP kinase, HIF-1α, and NF-κB pathway

In the present study, we sought to investigate the signal transduction pathways of expression of cytokines in the ethanol-stimulated human mast cell line, HMC-1. Ethanol significantly increased the intracellular calcium level in HMC-1. Ethanol also significantly enhanced IL-6, TNF-alpha, and TGF-beta 1 production compared with media control, but did not significantly affect the IL-1 beta production. After 8 h of stimulation, ethanol increased mRNA and protein expression levels of TNF-alpha and TGF-beta 1 in HMC-1. The increased cytokine level was significantly inhibited by BAPTA-AM, PD98059, and SB203580. These inhibitors also inhibited ethanol-induced ERK and p38 MAPK phosphorylation. Ethanol resulted in a great increase in protein levels and promoter activity driving luciferase expression of HIF-1 alpha and NF-kappa B in HMC-1 cells, but it did not affect on HIF-1 alpha mRNA expression. Our observations show that calcium, MAPK activation, HIF-1 alpha, and NF-kappa B are necessary for ethanol-induced TNF-alpha and TGF-beta 1 expression. These results may have important implications for the study of alcohol-related diseases. (c) 2005 Elsevier Inc. All rights reserved.