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KMID : 1025520090510060471
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Journal of Animal Science and Technology
2009 Volume.51 No. 6 p.471 ~ p.484
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Interferon Tau in the Ovine Uterus.
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Song Gwon-Hwa
Han Jae-Yong
Thomas E. Spencer
Bazer Fuller W.
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Abstract
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The peri-implantation period in mammals is critical with respect to survival of the conceptus(embryo/fetus and associated extraembryonic membranes) and establishment of pregnancy. During this period of pregnancy, reciprocal communication between ovary, conceptus, and endometrium is required for successful implantation and placentation. At this time, interferon tau(IFNT) is synthesized and secreted by the mononuclear trophectodermal cells of the conceptus between days 10 and 21~25. The actions of IFNT to signal pregnancy recognition and induce or increase expression of IFNT-stimulated genes (ISGs), such as ISG15 and OAS, are mediated by the Type I IFN signal transduction pathway. This article reviews the history, signaling pathways of IFNT and the uterine expression of several IFNT-stimulated genes during the peri-implantation period. Collectively, these newly identified genes are believed to be critical to unraveling the mechanism(s) of reciprocal fetal-maternal interactions required for successful implantation and pregnancy.
In eutherian mammals, including sheep, implantation of the blastocyst is a most important developmental event associated with viviparity(Spencer and Bazer, 2002; Spencer et al., 2004). During the peri-implantation period in the ovine uterus, the spherical blastocyst elongates to a tubular and then a filamentous form, and develops into a conceptus. At this time, interferon tau(IFNT) is synthesized and secreted by the mononuclear trophectodermal cells of the conceptus between days 10 and 21~25(maximally on days 14 to 16) (Ashworth and Bazer, 1989; Farin et al., 1989; Bazer, 1992; Roberts et al., 1999). In the ovine uterus, IFNT acts directly on the endometrial luminal epithelium(LE) and superficial ductal glandular epithelium(sGE) to suppress transcription of estrogen receptor alpha(ESR1) and oxytocin receptor(OXTR) genes(Spencer and Bazer, 1996; Fleming et al., 2001), thereby preventing production of luteolytic pulses of prostaglandin F2α(PGF)(Fig. 1).
During the estrous cycle, ESR1 expression increases and progesterone receptor(PGR) expression decreases on days 11 to 13, and subsequently estrogen(E2) induces OXTR expression on days 13 to 14(Wathes and Hamon, 1993; Spencer and Bazer, 1995). Thus, oxytocin from the posterior pituitary and/or corpus luteum(CL) can then induce release of luteolytic pulses of PGF on days 15 and 16(Hooper et al., 1986). During early pregnancy, IFNT produced by the elongating ovine conceptus suppresses ESR1 expression which then prevents ESR1-induced OXTR expression(Spencer and Bazer, 1996; Stevenson et al., 1994; Lamming et al., 1995; Spencer et al., 1995). Collectively, these indicate that the antiluteolytic actions of IFNT are to prevent increases in epithelial expression of E2-responsive ESR1, PGR, and OXTR gene by directly inhibiting transcription of the ESR1 gene and maintaining secretion of progesterone(P4) by the CL(Fleming et al., 2001; Fleming et al., 2006; Spencer et al., 2004).
In the ovine uterus, establishment and maintenance of pregnancy requires reciprocal communication between the ovary, conceptus, and endometrium by means of endocrine and paracrine signals during implantation and synepitheliochorial placentation(Spencer and Bazer, 2002). P4, the hormone of pregnancy, plays an important role in the establishment and maintenance of a uterine environment that supports conceptus development. Endometrial gland secretions, including growth factors, cytokines, and ions, are predominantly regulated by P4 (Spencer et al., 1999) and are required for peri-implantation conceptus
Fig.1.Schematic illustration of the current working hypothesis on hormonal regulation of the endometrial antiluteolytic mechanism and cross- talk between the conceptus and the maternal endometrium. During the estrous cycle, ESR1 expression increases and PGR expression decreases and then E2 induces OXTR expression, thereby allowing oxytocin from the posterior pituitary and/or CL to induce release of luteolytic pulses of PGF. In contrast, during early pregnancy, secreted IFNT from fully elongated conceptus silences ESR1 expression which prevents E2-induced OXTR expression. Legend: IFNT, interferon tau; IFNAR, Type I IFN receptor; PGR, progesterone receptor; ESR1, estrogen receptor alpha; OXTR, oxytocin receptor; IRF2, interferon regulatory factor 2; LE, luminal epithelium; sGE, superficial ductal glandular epithelium. (Adapted from Spencer et al., 2007.)
survival, elongation, and development (Gray et al., 2001; Gray et al., 2000). P4 acts via its cognate receptor, PGR. In the ovine endometrium, PGR are expressed in epithelia and stroma and allow P4 to directly regulate a variety of genes in the uterus. However, PGR expression is down-regulated by continuous exposure to P4 in ovine endometrial LE and GE after days 11 and 13 of pregnancy, respectively(Spencer and Bazer, 1995). The paradigm of loss of PGR in endometrial epithelia immediately before implantation is common to sheep (Spencer and Bazer, 2002; Spencer and Bazer, 1995), cattle (Kimmins and MacLaren, 2001), and pigs(Geisert et al., 1994), and other mammals studied to date including humans and mice(see review by (Spencer et al., 2004)).
During the peri-implantation period, uterine epithelial cell functions might be regulated by interactions between reprogrammed epithelial cells following down-regulation of PGR and specific factors produced by PGR-positive stromal cells in response to P4, and/or products of the conceptus such as IFNT, placental lactogen, and placental growth hormone (see review by Spencer et al., 2004). A large number of genes are induced by IFNT throughout the width of the uterine wall. These IFNT-stimulated genes(ISGs) are proposed to have biological roles in pregnancy recognition and uterine receptivity(Spencer and Bazer, 2002). In addition, induction of an antiviral state in the endometrium during early pregnancy may be beneficial by inhibiting sexually transmitted viruses as well as modulating local immune cells to promote tolerance of the allogeneic conceptus and stimulating production of cytokines beneficial for conceptus survival and growth (Hansen, 1995; Tekin and Hansen, 2002; Croy et al., 2003).
Collectively, knowledge of the complex, precisely orchestrated interaction between P4 and IFNT during the implantation period should provide new insights to improve fertility in humans and domestic animals, and provide key knowledge for interpreting cross-talk mechanisms between maternal endometrium and conceptus.
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KEYWORD
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Interferon tau, Progesterone, Sheep, Uterus, Implantation
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