Ethanol inhibits cytokine-induced iNOS and sPLA(2) in immortalized astrocytes: Evidence for posttranscriptional site of ethanol action

Chronic and excessive ethanol consumption is known to alter neuron and glia l cell functions in the central nervous system (CNS). Astrocytes comprise t he major cell type in the brain. These immune active cells are capable of r esponding to proinflammatory cytokines and endotoxins, which stimulate tran scriptional pathways leading to induction of genes, including the inducible nitric oxide synthase (iNOS) and secretory phospholipase A(2) (sPLA(2)). i n this study, we investigate the effects of ethanol on cytokine-induced iNO S and sPLA(2) in immortalized astrocytes (DITNC). When DITNC cells were exp osed to ethanol (0-200 mM) for 4 h prior to subsequent stimulation with cyt okines for 16 h, NO production decreased with increasing ethanol concentrat ions starting from 50 mM, At ethanol concentrations higher than 100 mM, eth anol also inhibited cytokine-induced sPLA(2) release into the culture mediu m. The inhibitory effect of ethanol on NO production corresponds well with the decrease in iNOS protein and NOS enzyme activity, but not with iNOS and sPLA(2) mRNA nor binding of NF-kappaB to DNA. The inhibition of cytokine-i nduced NO production by ethanol was also dependent on the time of ethanol e xposure to the cells, but addition of acetaldehyde up to 200 muM did not el icit any changes. Taken together, these results provide evidence for a post transcriptional mode of ethanol action on the cytokine induction pathway fo r NO production in astrocytes, Copyright (C) 2001 National Science Council, ROC end S. Karger AG, Basel.