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-gamma (IFN-gamma)). In particular, IFN-gamma 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-gamma transcription. Transient transfection assays in the human T lymphoblastoid cell line Jurkat demonstrated that the activation of the IFN-gamma 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-gamma 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-gamma promoter activity by RA. This element was found to be situated in a position of the IFN-gamma promoter close to a silencer element previously identified in our laboratory. These results suggest that direct modulation of IFN-gamma promoter activity is one of the possible mechanisms involved in the inhibitory effect of retinoids on IFN-gamma gene expression.

Mucosa-Specific Targets for Regulation of IFN-γ Expression: Lamina Propria T Cells Use Differentcis-Elements than Peripheral Blood T Cells to Regulate Transactivation of IFN-γ Expression

“…The proximal element has been shown to be a target for selective hypomethylation in cells that express IFN-␥ (43) and is believed to generate activation-specific expression in T-cell lines through binding of jun/ATF-2 heterodimers to this element (10). These sites are targets for selective inhibition of IFN-␥ gene transactivation after glucocorticoid treatment (8), but not following retinoid treatment (44,45). Additionally, whereas these sites are critical in regulation in PBL and T cell lines, they are of modest importance in modulating CD2 response in LPMC.…”

The Cyclopentenone-Type Prostaglandin 15-Deoxy-Δ12,14-Prostaglandin J2 Inhibits CD95 Ligand Gene Expression in T Lymphocytes: Interference with Promoter Activation Via Peroxisome Proliferator-Activated Receptor-γ-Independent Mechanisms

“…In particular, the role of specific activators of hormone nuclear receptors has been studied in these cells, and they were shown as useful and powerful modulators of proinflammatory cytokines and surface receptor ligands (27)(28)(29)(30).…”

An IFNG SNP with an estrogen-like response element selectively enhances promoter expression in peripheral but not lamina propria T cells

“…Surprisingly, two putative hormone response elements, retinoic acid and estrogen receptor binding motifs, which belong to the nuclear receptor superfamily of hormoneinducible transcription factors, had also been generated by the À179T allele. These were of particular interest in light of early studies, which had identified regulation of IFNG promoter expression by glucocorticoids, as well as vitamins A and D. 20,21 Competition experiments were carried out with consensus oligonucleotides to the various potential cis-acting elements (Figure 4). Table 1 summarizes the results of these experiments.…”

“…Early studies have established transcriptional binding sites modulating IFN-g expression through members of the nuclear hormone receptor family such as glucocorticoid, vitamin D 3 and retinoic acid. 20,21,31 The estrogen receptor is an inducible trans-activating protein, which initiates transcription through the binding to DNA response elements defined as EREs, following exposure to estrogen. Hormone response elements for the various hormones, such as glucocorticoids, retinoic acid and estrogen, share sequence homology similarities, although each possesses distinct DNA binding sequence requirements.…”