The newly described 1A promoter of the human glucocorticoid receptor (hGR) (1) gene contains an interferon regulatory factor element (IRF-E), a binding motif for the family of proteins termed interferon regulatory factors (IRFs) that are regulated by interferons. To examine the in vivo role of interferons (IFNs) in hGR gene regulation, human T-cell lines (CEM-C7 and Jurkat) were treated with IFN. IFN rapidly induces the expression of IRF-1 proteins in a dose- and time-dependent manner. Luciferase expression is induced by IFN treatment in Jurkat cells transfected with an hGR 1A promoter IRF-E/luciferase reporter gene, but induction is lost with deletion of the IRF-E. Electrophoretic mobility shift and supershift analyses indicate an increase in the binding of IRF-1 to oligonucleotides containing the hGR 1A promoter IRF-E following IFN treatment, while IRF-2 binding to this oligonucleotide is unchanged. Human IRF-1 and IRF-2 proteins expressed in Chinese hamster ovary cells bind to the hGR 1A promoter IRF-E; however only IRF-1 activates transcription. Although IFNs clearly activate a transfected reporter gene containing the hGR 1A promoter in T-cells, they do not alter the sensitivity of CEM-C7 cells to glucocorticoid-induced apoptosis. Further studies revealed that the glucocorticoid steroid hormone, dexamethasone, completely blocks interferon induction of IRF-1 mRNA levels. This could explain the lack of any greater apoptotic response to a combination of dexamethasone plus interferon, compared with the response obtained by dexamethasone alone. In addition, treatment with IFN alone does not alter endogenous GR mRNA levels (including exon 1A-containing transcripts derived from the hGR 1A promoter) in T-lymphoblast cells, even though IRF-1 levels are induced. The difference in IRF-1 driven transcription between the hGR 1A reporter construct and the endogenous hGR 1A promoter could potentially be due to epigenetic effects, such as methylation.