Interferon gamma (IFN-)plays a role in a variety of lung inflammatory responses and corticosteroids are frequently employed as a treatment in these conditions. Therefore, the effect of IFN-, of the corticosteroid, dexamethasone (dex) or both on gene expression was studied in normal human bronchial epithelial (NHBE) cells. NHBE cells were exposed to medium alone, IFN- (300 U/ml), dex (10^-7 M) or both IFN- and dex for 8 or 24 hours. mRNA was extracted and gene expression was examined using oligonucleotide microarrays (Affymetrix HG-U95Av2). A principal components analysis demonstrated that the IFN- treatment effect was the primary source of differences in the data. Using a 5% false discovery rate, of the 66 genes upregulated by IFN- by two-fold or greater at 8 hours and 287 (252 annotated by function) genes upregulated at 24 hours, coincubation with dex inhibited the expression of 2 genes at 8 hours and 45 genes at 24 hours. Prominent among these genes were cytokines and secreted proteins. In contrast, dex cotreatment increased expression of 65 of the 376 (312 annotated by function) genes that were inhibited by IFN- by 50% at 24 hours. The majority of these genes encode cell cycle or nuclear proteins. In contrast to the large number of genes altered by IFN- treatment of NHBE cells, dex alone increased the expression of only 22 genes and inhibited the expression of 7 genes compared to controls at 24 hours. For a selected group of genes, data obtained from microarray were confirmed using real-time PCR expression quantification; protein expression was confirmed using ELISA. This study demonstrates that over 600 genes are altered by IFN- in NHBE cells. The effect of dex on IFN- induced changes suggests a specific, targeted effect on IFN- responses that is substantially greater than the effect of dex alone. Further, dex had little effect on the immediate early response to IFN-, but a significant effect on the delayed, late responses at 24 hours. These data may help to further understand the selective effects of glucocorticosteroid treatment on inflammatory processes.