Hum. Reprod. Advance Access originally published online on May 9, 2006
Human Reproduction 2006 21(10):2538-2544; doi:10.1093/humrep/del126
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Progesterone regulates HLA-G gene expression through a novel progesterone response element
Department of Gynecology and Obstetrics, Sunnybrook and Women’s College Health Sciences Center, Toronto, Ontario, Canada
1 To whom correspondence should be addressed at: 790 Bay Street, Suite 1100, Toronto, Ontario, Canada M5G 1N8. E-mail: cliffl{at}ican.net
BACKGROUND: We have previously demonstrated that progesterone has a stimulatory effect on HLA-G gene expression. Because this effect was abolished by the anti-progestin, RU486, we hypothesize that this effect is through receptor-mediated up-regulation of the HLA-G gene. The objective of this study was to explore the molecular mechanisms of this effect. METHODS: The transient transfection of a chloramphenicol acetyltransferase (CAT) construct containing a fragment of the HLA-G gene promoter into the JEG-3 choriocarcinoma cell line was performed. An electrophoretic mobility shift assay (EMSA) and a DNA fragment-binding enzyme-linked immunosorbent assay (ELISA) were carried out to locate a specific progesterone response element (PRE) in the HLA-G gene promoter region. RESULTS: Progesterone treatment of JEG-3 cells transfected with the HLA-G gene promoter-CAT construct resulted in an increase of CAT synthesis, whereas RU486 blocked this transcriptional activation. A novel PRE-binding site sequence, with 60% homology to that of wild-type mouse mammary tumour virus (MMTV) PRE, was discovered in this region. CONCLUSION: The effect of progesterone on HLA-G gene expression is through progesterone receptor (PR) activation, followed by binding to a novel PRE in the HLA-G promoter region. Therefore, one of the mechanisms of immunomodulation by progesterone during pregnancy may be through the regulation of HLA-G gene expression via this novel PRE.
Key words: gene regulation/HLA-G/novel progesterone response element/pregnancy/progesterone
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