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.