Influence of IFN-γ on gene expression in normal human bronchial epithelial cells: modulation of IFN-γ effects by dexamethasone

Abstract

-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 of 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 Ϫ7 M), or both IFN-␥ and Dex for 8 or 24 h. Gene expression was examined using oligonucleotide microarrays. A principal components analysis demonstrated that the IFN-␥ treatment effect was the primary source of differences in the data. With a 5% false discovery rate, of the 66 genes upregulated by IFN-␥ 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-␥ 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-␥-induced changes suggests a specific, targeted effect on IFN-␥ responses that is substantially greater than the effect of Dex alone. Dex had little effect on the immediate early response to IFN-␥ but a significant effect on the late responses.

DUSP1 Maintains IRF1 and Leads to Increased Expression of IRF1-dependent Genes

“…12C). Despite dexamethasone-dependent repression varying considerably for the different late-phase genes (38,58,59), this statement also appears to hold true, even for the more highly repressed mRNAs (data not shown). Thus, the repression by dexamethasone on these genes must primarily involve mechanisms other than IRF1 (Fig.…”

Update on glucocorticoid action and resistance

“…176 Microarray studies in human bronchial epithelial cells indicate that dexamethasone is not very effective at suppressing IFN-g-stimulated gene expression at 8 hours (2/66 genes) and 24 hours (45/287 genes). 177 Furthermore, many of the genes suppressed by dexamethasone at later time points were secondary, not primary, genes stimulated by proteins upregulated by IFN-g. This inability of dexamethasone to affect IFN-g-stimulated functions might be both temporal and cell specific because dexamethasone was able to suppress IFN-g-stimulated STAT1 activity in monocytes, but not in T cells, and many of the suppressive effects of dexamethasone required several days' preincubation to become apparent.…”

“…199 Small-molecule inhibitors of IKK-2 are in development, 230 and recent evidence suggests that IKK2 inhibitor can prevent activation of inflammation induced by IFN-g, 231 an event that is in part glucocorticoid insensitive. 177 There are worries about possible side effects of these drugs, such as increased susceptibility to infections; however, as a corollary to this, if either glucocorticoids or aspirin were discovered today, they would be unlikely to be used in human subjects because of their low therapeutic ratio and their side effect profile. Inhibition of specific coactivators activated by NF-kB might prove to be useful targets, especially if they also repress the action of other proinflammatory transcription factors.…”

Evolution to a Chronic Disease Niche Correlates with Increased Sensitivity to Tryptophan Availability for the Obligate Intracellular Bacterium Chlamydia pneumoniae

“…Exposure of the host cells to IFN-␥ results in induction of a myriad of responses (81). However, it is the induction of IDO (indoleamine 2,3-dioxygenase) (82) and inducible nitric oxide synthase (iNOS) (83) and downregulation of transferrin receptors (84) that is central to intracellular inhibition of chlamydial growth.…”