Pregnancy and interferon tau regulate RSAD2 and IFIH1 expression in the ovine uterus

Abstract

Radical S-adenosyl methionine domain containing 2 (RSAD2) encodes a cytoplasmic antiviral protein induced by interferons (IFN). Interferon-induced with helicase C domain 1 (IFIH1) is a RNA helicase involved in innate immune defense against viruses, growth suppression, and apoptosis. Interferon tau (IFNT), a Type I IFN produced by the peri-implantation ruminant conceptus, acts on the uterine endometrium to signal pregnancy recognition and promote receptivity to implantation. Transcriptional profiling identified RSAD2 and IFIH1 as IFNT regulated genes in the ovine uterine endometrium. This study tested the hypothesis that RSAD2 and IFIH1 were induced in the endometrium in a cell type-specific manner by IFNT from the conceptus during early pregnancy. Endometrial RSAD2 and IFIH1 mRNA increased between days 12 and 16 of pregnancy, but not of the estrous cycle. In pregnant ewes, RSAD2 and IFIH1 mRNAs increased in endometrial glands, and stroma and immune cells, but not in the luminal epithelium. Neither gene was expressed in the trophectoderm of day 18 or 20 conceptuses. Progesterone (P4) treatment of ovariectomized ewes did not induce expression RSAD2 or IFIH1 mRNA in the endometrium; however, intrauterine injections of IFNT induced expression of RSAD2 and IFIH1 mRNA in endometria of ewes treated with P4, as well as in ewes treated with P4 and the progesterone receptor antagonist, ZK 136,317. These results indicate that conceptus IFNT induces both RSAD2 and IFIH1 in a P4-independent manner in the ovine uterine endometrium. These two IFNT-stimulated genes are proposed to have biological roles in the establishment of uterine receptivity to the conceptus during implantation through induction of an antiviral state and modulation of local immune cells in the endometrium.

BVDV alters uterine prostaglandin production during pregnancy recognition in cows

“…During early pregnancy or following intrauterine IFN treatment, the expression of the majority of progesterone-independent ISGs such as RSAD2 (radical S-adenosyl methionine domain containing 2) and IFIH1 (interferon-induced with helicase C domain 1) was increased in endometrial stroma, glands and immune cells but not in the luminal epithelium. In contrast, some non-classical ISGs such as LGALS15 (galectin 15), CTSL (cathespin L) and CST3 (cystatin C), which require progesterone priming, were predominantly expressed in the endometrial luminal epithelium and superficial glandular epithelium (Song et al 2007, Bazer et al 2008.…”

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

“…As illustrated in Figs 1-3 and summarized in Supplementary Table 1, numerous ISGs are induced or stimulated in the endometrium during conceptus elongation in both cattle and sheep. Curiously, in vivo studies revealed that many classical ISGs (b-2-microglobulin (B2M), guanylate-binding protein 2 (GBP2), interferon, a-inducible protein 27 (IFI27), interferon-induced protein with tetratricopeptide repeats 1 (IFIT1), interferonstimulated gene 15 (ISG15), IRF9, MHC class I polypeptide (MIC), 2 0 ,5 0 -oligoadenylate synthetase (OAS), radical S-adenosyl methionine domain containing 2 (RSAD2), STAT1, and STAT2) are not induced or upregulated by IFNT in endometrial LE of the ovine uterus (Johnson et al 1999b, Kim et al 2003, Song et al 2007). This finding was initially surprising, because all endometrial cell types express IFNAR1 (interferon (a, b, and u) receptor 1) and IFNAR2 subunits of the common type I IFNAR (Rosenfeld et al 2002).…”

Progesterone and interferon tau regulate leukemia inhibitory factor receptor and IL6ST in the ovine uterus during early pregnancy

“…CX proteins were prepared for intrauterine injection as described previously (Spencer et al 1995). This regimen of P4 and roIFNT mimics the effects of P4 from the CL and IFNT from the conceptus on endometrial expression of hormone receptors and ISGs during early pregnancy in sheep (Song et al 2005(Song et al , 2006a(Song et al , 2007(Song et al , 2008a(Song et al , 2008b. All ewes were hysterectomized on day 17, and uteri processed as described for study 1.…”