Retinoic acid-induced transcriptional modulation of the human interferon-γ promoter

Abstract

Disregulation of vitamin A metabolism is able to generate different immunological effects, including altered response to infection, reduced IgG production, and differential regulation of cytokine gene expression (including interleukin-2 and -4 and interferon-γ (IFN-γ)). In particular, IFN-γ gene expression is significantly affected by vitamin A and/or its derivatives (e.g. retinoic acid (RA)). Here, we analyze the effect of retinoic acid on IFN-γ transcription. Transient transfection assays in the human T lymphoblastoid cell line Jurkat demonstrated that the activation of the IFN-γ promoter was significantly down-regulated in the presence of RA. Surprisingly, two different AP-1/CREB-ATF-binding elements situated in the initial 108 base pairs of the IFN-γ promoter and previously shown to be critical for transcriptional activity were unaffected by RA. Utilizing promoter deletions and electrophoretic mobility shift analysis, we identified a USF/EGR-1-binding element cooperating in the modulation of IFN-γ promoter activity by RA. This element was found to be situated in a position of the IFN-γ promoter close to a silencer element previously identified in our laboratory. These results suggest that direct modulation of IFN-γ promoter activity is one of the possible mechanisms involved in the inhibitory effect of retinoids on IFN-γ gene expression.