Influence of IFN-gamma on gene expression in normal human bronchial epithelial cells: modulation of IFN-gamma effects by dexamethasone.
Interferon gamma (IFN-gamma) 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-gamma, of the corticosteroid dexamethasone (Dex), or of both on gene expression was studied in normal human bronchial epithelial (NHBE) cells. NHBE cells were exposed to medium alone, IFN-gamma (300 U/ml), Dex (10(-7) M), or both IFN-gamma and Dex for 8 or 24 h. Gene expression was examined using oligonucleotide microarrays. A principal components analysis demonstrated that the IFN-gamma treatment effect was the primary source of differences in the data. With a 5% false discovery rate, of the 66 genes upregulated by IFN-gamma by twofold or greater at 8 h and 287 genes upregulated at 24 h, coincubation with Dex inhibited the expression of 2 genes at 8 h and 45 genes at 24 h. Prominent among these were cytokines and secreted proteins. Dex cotreatment increased expression of 65 of the 376 genes that were inhibited by IFN-gamma by 50% at 24 h. The majority of these genes encode cell cycle or nuclear proteins. Dex alone increased the expression of only 22 genes and inhibited the expression of 7 genes compared with controls at 24 h. The effect of Dex on IFN-gamma-induced changes suggests a specific, targeted effect on IFN-gamma responses that is substantially greater than the effect of Dex alone. Dex had little effect on the immediate early response to IFN-gamma but a significant effect on the late responses.
Critical Care Medicine Department, National Institutes of Health, Bethesda, Maryland 20892, USA.
Rafal
R
Pawliczak
Carolea
C
Logun
Patricia
P
Madara
Jennifer
J
Barb
Anthony F
AF
Suffredini
Peter J
PJ
Munson
Robert L
RL
Danner
James H
JH
Shelhamer
D000305:Adrenal Cortex Hormones / Q000378:metabolism; D001980:Bronchi / Q000166:cytology* / Q000378:metabolism; D002453:Cell Cycle; D002454:Cell Differentiation; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D018946:Chemokine CCL5 / Q000378:metabolism; D016000:Cluster Analysis; D003470:Culture Media / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004847:Epithelial Cells / Q000378:metabolism*; D015870:Gene Expression; D005786:Gene Expression Regulation; D005938:Glucocorticoids / Q000378:metabolism; D006801:Humans; D007249:Inflammation; D007371:Interferon-gamma / Q000737:chemistry / Q000378:metabolism*; D007372:Interferons / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D009841:Oligonucleotides / Q000737:chemistry; D011786:Quality Control; D011994:Recombinant Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism; D013997:Time Factors; D014158:Transcription, Genetic; D015854:Up-Regulation
D000305:Adrenal Cortex Hormones; D018932:Chemokine CCL2; D018946:Chemokine CCL5; D003470:Culture Media; D016207:Cytokines; D005938:Glucocorticoids; D009841:Oligonucleotides; D011994:Recombinant Proteins; D003907:Dexamethasone; D007371:Interferon-gamma; D007372:Interferons