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Progesterone Regulation of the Mammalian Ortholog of Methylcitrate Dehydratase (Immune Response Gene 1) in the Uterine Epithelium during Implantation through the Protein Kinase C Pathway

Departments of Developmental and Molecular Biology and Obstetrics, Gynecology and Women’s Health, Center for the Study of Reproductive Biology and Women’s Health, Albert Einstein College of Medicine, New York, New York 10461

Address all correspondence and requests for reprints to: Jeffrey Pollard, Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, New York, New York 10461. E-mail: pollard{at}aecom.yu.edu.

Implantation requires coordination between development of the blastocyst and the sex steroid hormone-regulated differentiation of the uterus. Under the influence of these hormones, the uterine luminal epithelium becomes receptive to attachment of the hatched blastocyst. In this study we sought to identify genes regulated by progesterone (P₄) in the uterine epithelium. This resulted in the identification of one novel P₄-regulated gene that had been previously found in lipopolysaccharide-stimulated macrophages and called immune response gene-1 (Irg1) and which is the mammalian ortholog of the bacterial gene encoding methylcitrate dehydratase. In adult mice Irg1 expression was limited to the uterine luminal epithelium where it is expressed only during pregnancy with a peak coinciding with implantation. Irg1 mRNA expression is regulated synergistically by P₄ and estradiol (E₂) but not by E₂ alone. In macrophages Irg1 is induced by lipopolysaccharide through a protein kinase C (PKC)-regulated pathway. Now we demonstrate that the PKC pathway is induced in the uterine epithelium at implantation by the synergistic action of P₄ and E₂ and is responsible for the hormone induction of Irg1. These results suggest that the PKC pathway plays an important role in modulating steroid hormone responsiveness in the uterine luminal epithelium during the implantation window and that Irg1 will be an important marker of this window and may play an important role in implantation.

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Ligands:   17β-Estradiol  |  Progesterone

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