Retinoic acid-induced transcriptional modulation of the human interferon-gamma promoter.
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.
Intramural Research Support Program, Scientific Application International Corporation Frederick, Frederick, Maryland 21702-1201, USA.
M
M
Cippitelli
J
J
Ye
V
V
Viggiano
A
A
Sica
P
P
Ghosh
A
A
Gulino
A
A
Santoni
H A
HA
Young
D006801:Humans; D007371:Interferon-gamma / Q000235:genetics*; D015759:Ionomycin / Q000494:pharmacology; D019169:Jurkat Cells; D009154:Mutation; D009687:Nuclear Proteins / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D017384:Sequence Deletion; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects*; D014212:Tretinoin / Q000378:metabolism / Q000494:pharmacology*
D009687:Nuclear Proteins; D018168:Receptors, Retinoic Acid; D015759:Ionomycin; D014212:Tretinoin; D007371:Interferon-gamma; D013755:Tetradecanoylphorbol Acetate