Ovine Interferon-τ Regulates Expression of Endometrial Receptors for Estrogen and Oxytocin but not Progesterone1

Spencer, Thomas E.; Becker, Walter A.; George, Philip; Mirando, Mark A.; Ogle, Thomas F.; Bazer, Fuller W.

doi:10.1095/biolreprod53.3.732

Cited by 131 publications

(91 citation statements)

References 54 publications

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“…Proteins were prepared for IU injection as described previously (Spencer et al 1999b). This regimen of P4 and IFNT mimics the effects of P4 and the conceptus on endometrial expression of hormone receptors and IFNT-stimulated genes during early pregnancy in ewes (Spencer et al 1995, Kim et al 2003. All ewes were hysterectomized on day 17.…”

Section: Studymentioning

confidence: 99%

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

Song¹,

Bazer²,

Spencer³

2007

Reproduction

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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.

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Section: Studymentioning

confidence: 99%

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

Song¹,

Bazer²,

Spencer³

2007

Reproduction

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“…However, IFNτ does not prevent down-regulation of progesterone receptor levels that resulted from continuous injections of progesterone [57,60], but suppressed the estrogeninduced ER and OTR gene expression [61]. Therefore, the antiluteolytic effect exhibited by IFNτ in the endometrium is due to IFNτ preventing ER expression and subsequently estrogen-induced OTR expression [60,61].…”

Section: Biological Properties Of Ifnτ τ τ τmentioning

confidence: 99%

“…Intra-uterine injection of IFNτ causes the downregulation of OTR, ER and oxytocin-induced PGF2α production [55][56][57][58][59]. However, IFNτ does not prevent down-regulation of progesterone receptor levels that resulted from continuous injections of progesterone [57,60], but suppressed the estrogeninduced ER and OTR gene expression [61].…”

Section: Biological Properties Of Ifnτ τ τ τmentioning

confidence: 99%

Regulation of Interferon-.TAU. Gene Expression and the Maternal Recognition of Pregnancy.

Yamaguchi

Nagaoka

Matsuda

et al. 2001

Journal of Reproduction and Development

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Abstract. In order for pregnancy to be established, the maternal system must recognize the presence of a conceptus(es) within the uterus. This physiological phenomenon, which subsequently causes the extension of the corpus luteum (CL) life-span, is known as maternal recognition of pregnancy. In ruminant ungulates, interferon-tau (IFNτ), produced by the conceptus, binds to the receptor located in the maternal endometrium in a paracrine manner. Its binding then affects levels of endometrial oxytocin receptor and estrogen receptor, which reduces pulsatile secretion of a luteolysin, prostaglandin F2α, resulting in the extension of CL function. Production of IFNτ seems to parallel the degree of trophoblast elongation and as the conceptus begins its attachment to the endometrium, IFNτ levels decline rapidly. Involvement of IFNτ in the process of implantation has long been suspected, but a role for IFNτ other than CL extension or transcriptional regulation of IFNτ genes has not been elucidated. In fact, several transcription factors that regulate the expression of IFNτ have been found, but none could explain its unique regulation. Recent findings related to maternal recognition of pregnancy are presented herein and a new insight into the potential regulation of IFNτ is discussed.

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“…It acts in a paracrine manner on the endometrium to establish and maintain pregnancy by suppressing the normal pattern of pulsatile release of uterine PFG 2α leading to luteolysis at the end of the estrous cycle. Several studies in the ewe have shown that IFNτ suppresses cyclic increases of the estrogen receptor gene transcription and thereby prevents estrogen induced increases in oxytocin receptor gene expression, which normally occurs in cyclic ewes undergoing luteolysis (Knickerbocker et al, 1986;Spencer et al, 1995).…”

Section: Maternal Recognition Of Pregnancy and The Pivotal Role Of Ifmentioning

confidence: 99%

“…Even though one may assume, IFNτ does not act to stabilize or prevent autologous downregulation of the progesterone receptor mRNA and protein expression in the endometrium, which normally occurs towards the end of the estrous cycle (Spencer et al, 1995).…”

Section: Maternal Recognition Of Pregnancy and The Pivotal Role Of Ifmentioning

confidence: 99%

2 Identification of Genes Induced by the Conceptus in the Bovine Endometrium During the Pre-Implantation Period

Klein¹,

Bauersachs²,

Ulbrich³

et al. 2006

Reprod. Fertil. Dev.

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Early embryonic development, implantation, and maintenance of a pregnancy are critically dependent on an intact embryo-maternal communication. So far, only few signals involved in this dialogue have been identified. In ruminants, interferon tau (IFN�) plays a key role in the process of maternal recognition of pregnancy by exhibiting antiluteolytic activity. Even though many experimental findings indicate a pivotal role of IFN� in the context of embryo-maternal communication in ruminants, a number of other systems may be involved. To identify genes induced in the bovine endometrium by the signaling of the embryo, a combination of subtracted cDNA libraries and cDNA array hybridization was applied. Monozygotic twin pairs (n = 5) were used as the biological model. Pregnancy was created in one twin by transferring two in vitro-produced embryos on Day 7 of the estrous cycle; the other twin received a sham embryo transfer. Pregnant and nonpregnant twins were slaughtered at Day 18; endometrial tissue samples were recovered and processed for transcriptome analysis as described (Bauersachs et al. 2005 J. Mol. Endocrinol. 34, 889-908). Screening of 4608 clones of two subtracted libraries revealed 90 different up-regulated genes and mRNAs, of which almost 50% are known to be stimulated by type I interferons. Among these interferon-stimulated genes, the ISG15 system is assumed to be of particular interest, and several components were studied in more detail using in situ hybridization. The pattern of mRNA expression suggests that modification of endometrial proteins through ISG15ylation plays a fundamental role during the pre-implantation period. A classification of the identified genes based on Gene Ontologies revealed the prevalence of genes involved in regulation of gene expression, cell communication, cell growth, cell differentiation, cell proliferation, and cell adhesion, and also the prevalence of genes with immune-related functions. These results underline the intense response of the endometrium to the presence of a conceptus, culminating in the preparation of the maternal environment for embryonic implantation. Further, for eleven selected genes the expression in the endometrium was quantified by the use of real-time RT-PCR. Overall, the results of quantitative RT-PCR and array hybridization correlated very well. To our knowledge this study provides the first holistic gene expression analysis of the bovine endometrium during the pre-implantation period. The results underline the importance of IFN� as an embryo-derived pregnancy recognition signal and depict the molecular mechanisms at the mRNA level underlying the intense embryo-maternal dialog taking place at Day 18 of gestation.

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Ovine Interferon-τ Regulates Expression of Endometrial Receptors for Estrogen and Oxytocin but not Progesterone1

Cited by 131 publications

References 54 publications

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

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

Regulation of Interferon-.TAU. Gene Expression and the Maternal Recognition of Pregnancy.

2 Identification of Genes Induced by the Conceptus in the Bovine Endometrium During the Pre-Implantation Period

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