Immune-Responsive Gene 1 Is a Novel Target of Progesterone Receptor and Plays a Critical Role during Implantation in the Mouse

Abstract

The steroid hormone progesterone (P) is a critical regulator of uterine receptivity during blastocyst implantation. The hormone acts through nuclear P receptors (PRs) to modulate the expression of specific gene networks in various uterine cell types. To identify the P-regulated pathways underlying uterine receptivity, we previously used oligonucleotide microarrays to analyze uterine mRNA profiles at the time of implantation in response to RU486, a PR antagonist. We reported that the mRNA corresponding to the immune-responsive gene 1 (Irg1), a previously described lipopolysaccharide-inducible gene, is one of the several mRNAs that are markedly down-regulated by RU486 in the preimplantation uterus. In the present study, we performed in situ hybridization to show that P stimulates Irg1 mRNA synthesis in the luminal epithelial cells of uteri of ovariectomized wild-type but not PR knockout mice. We also report that Irg1 mRNA was induced in the luminal epithelium of pregnant uterus between d 3 and 5, overlapping the window of implantation. To investigate the function of Irg1 during implantation, we administered sense or antisense oligodeoxynucleotides into preimplantation mouse uteri. Treatment with antisense oligodeoxynucleotides led to suppression in Irg1 mRNA expression without affecting unrelated mRNAs in the pregnant uterus. This intervention was also accompanied by impairment in embryo implantation, indicating that the phenotype is linked to the suppression of Irg1 mRNA. Collectively, our studies identified Irg1 as a novel target of PR in the pregnant uterus and also revealed that it is a critical regulator of the early events leading to implantation.

Inhibition of Stat3 activation in the endometrium prevents implantation: A nonsteroidal approach to contraception

“…Only Irg1, however, is believed to be important for implantation because down-regulation by antisense oligonucleotides is associated with decreased implantation (36). We have now shown that up-regulation of these genes by LIF in the LE depends, at least in part, on the activation of Stat3.…”

Genes involved in conceptus–endometrial interactions in ruminants: insights from reductionism and thoughts on holistic approaches

“…Since expression of ISGs increases in a stage-specific manner within endometria of diverse species, including domestic animals, laboratory rodents, primates, and humans during early pregnancy, they may be universally important in establishment of uterine receptivity to conceptus implantation (Li et al 2001, Austin et al 2003, Cheon et al 2003, Bany & Cross 2006, Hess et al 2007, Kashiwagi et al 2007. A number of transcriptional profiling experiments conducted with human cells, ovine endometrium, and bovine endometrium have elucidated genes regulated by IFNT during pregnancy (Kim et al 2003, Sandra et al 2005, Chen et al 2006, Gray et al 2006, Klein et al 2006; see Supplementary Table 1 and Figs 1 and 2 for summary and interpretation).…”

Immune-responsive gene 1 protein links metabolism to immunity by catalyzing itaconic acid production

“…Irg1 was originally identified as a 2.3-kb cDNA from a library synthesized from mRNA isolated from a murine macrophage cell line after LPS stimulation (12). Irg1 is also highly expressed in the early events leading to implantation in the pregnant uterus (13,14), the specific phase in which a high level of inflammatory cytokines are secreted by the endometrial cells as well as by cells of the immune system that are recruited to the site of implantation (15). Interestingly, Irg1 has been used to classify functional profiles of neurotoxic C-C chemokine receptor 9 + Irg1 + and neurosupportive C-X-C chemokine receptor 3 + Irg1 − microglia in vivo (16).…”