Brief alcohol exposure alters transcription in astrocytes via the heat shock pathway

Astrocytes are critical for maintaining homeostasis in the central nervous system (CNS), and also participate in the genomic response of the brain to drugs of abuse, including alcohol. In this study, we investigated ethanol regulation of gene expression in astrocytes. A microarray screen revealed that a brief exposure of cortical astrocytes to ethanol increased the expression of a large number of genes. Among the alcohol‐responsive genes (ARGs) are glial‐specific immune response genes, as well as genes involved in the regulation of transcription, cell proliferation, and differentiation, and genes of the cytoskeleton and extracellular matrix. Genes involved in metabolism were also upregulated by alcohol exposure, including genes associated with oxidoreductase activity, insulin‐like growth factor signaling, acetyl‐CoA, and lipid metabolism. Previous microarray studies performed on ethanol‐treated hepatocyte cultures and mouse liver tissue revealed the induction of almost identical classes of genes to those identified in our microarray experiments, suggesting that alcohol induces similar signaling mechanisms in the brain and liver. We found that acute ethanol exposure activated heat shock factor 1 (HSF1) in astrocytes, as demonstrated by the translocation of this transcription factor to the nucleus and the induction of a family of known HSF1‐dependent genes, the heat shock proteins (Hsps). Transfection of a constitutively transcriptionally active Hsf1 construct into astrocytes induced many of the ARGs identified in our microarray study supporting the hypothesis that HSF1 transcriptional activity, as part of the heat shock cascade, may mediate the ethanol induction of these genes. These data indicate that acute ethanol exposure alters gene expression in astrocytes, in part via the activation of HSF1 and the heat shock cascade. The presence of ethanol alters the redox state of astrocytes, triggering an increase in expression of genes related to oxidoreductases, antioxidants, stress, and apoptosis. We also observed the regulation of genes that control the immune response, as well as those involved in acetyl‐CoA and lipid metabolism. The data presented in this work suggest that a significant subset of the astrocyte alcohol‐sensitive genes are regulated by HSF1, perhaps via the genetic alcohol‐responsive element (ARE).