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a Department of Animal Science and Center for Animal Biotechnology and Genomics, Albert B. Alkek Institute of Biosciences and Technology, Texas A&M University System Health Science Center, College Station, Texas 77843-2471
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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) is the antiluteolytic signal produced by the conceptus of ruminants. Intrauterine administration of recombinant ovine IFN suppresses expression of endometrial estrogen receptor (ER) and oxytocin receptor (OTR) in the luminal and superficial glandular epithelia to abrogate the production of luteolytic prostaglandin F2
(PGF2) pulses. Subcutaneous (s.c.) injections of recombinant ovine (o) IFN appear to extend the interestrous interval by altering uterine PGF2 response to oxytocin. The present study tested the hypothesis that antiluteolytic effects of roIFN injected into the uterine lumen (paracrine) or s.c. (endocrine) are equivalent in suppressing expression of endometrial ER and OTR and inducing uterine expression of type I IFN-regulated Mx and ubiquitin cross-reactive proteins (UCRP). Sixteen cyclic ewes were fitted with uterine catheters on Day 5 (Day 0 = estrus), were assigned randomly to receive treatment with control proteins or roIFN (2 x 107 antiviral units/day) by either intrauterine or s.c. injections from Days 11 to 15, and were ovariohysterectomized on Day 16. Results indicated that expression of ER and OTR mRNAs in endometrial epithelium was suppressed by intrauterine but not by s.c. injections of roIFN. Intrauterine injections of roIFN increased expression of Mx and UCRP mRNA in the endometrium. Subcutaneous injections of roIFN increased endometrial Mx mRNA levels but not UCRP mRNA. Unexpectedly, intrauterine and s.c. injections of roIFN were equally effective in inducing expression of Mx and UCRP mRNA in the corpus luteum. Although s.c. injections of roIFN induced Mx mRNA in the endometrial epithelium, s.c. injections of roIFN did not abrogate activation of the uterine luteolytic mechanism by suppressing epithelial ER and OTR expression. Therefore, results of this study failed to support the assumption that endocrine roIFN mimics antiluteolytic effects of paracrine IFN to improve pregnancy rates in sheep.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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) is secreted by trophectoderm of ovine conceptuses (embryo and associated membranes) between Days 12 and 21 of pregnancy [2] and binds to type I IFN receptors on luminal and superficial glandular endometrial epithelium. Ovine IFN serves as an antiluteolytic signal for pregnancy recognition by preventing uterine release of luteolytic pulses of prostaglandin F2 (PGF2) [2, 3]. Available evidence indicates that 1) oIFN is the primary conceptus signal for pregnancy recognition in ruminants, 2) neither the presence of the conceptus nor intrauterine injections of roIFN stabilize endometrial expression of progesterone receptors (PR), and 3) roIFN or presence of the conceptus prevents endometrial expression of estrogen receptor (ER) and oxytocin receptor (OTR) genes to block development of the uterine luteolytic mechanism [2–4]. In addition to its role in pregnancy recognition, IFN possesses antiviral, antiproliferative, and immunomodulatory activities similar to those of other type I IFNs [5–7]. IFN increases uterine expression of 2',5' oligoadenylate synthetase [8], ß2-microglobulin [9], interferon regulatory factor-1 (IRF-1) and IRF-2 [10], ubiquitin cross-reactive protein (UCRP) [11–13], and Mx protein [14]. Interestingly, granulocyte chemotactic protein-2 (GCP) is induced in bovine uterine cells by IFN but not by IFN [15], suggesting that IFN can activate pathways common to other type I IFNs and novel IFN-induced signaling pathways.
Ovine IFN shares amino acid sequence homology and biological activities with bovine (b) IFN, human (h) IFN, and hIFN
[16–20]. Radiolabeled recombinant (r) hIFN and rbIFN bind receptors on the ovine endometrium and are displaced equally by either rbIFN or oIFN [17], suggesting that these related IFNs function as IFN agonists that might be used to supplement the signal for pregnancy recognition. However, attempts to use rbIFN to increase fertility in ruminants by delaying or preventing luteolysis have provided equivocal results. This may be due to differences in biological activities among the type I IFNs tested, route and duration of administration, and/or signal transduction pathways activated. Supplementation of inseminated animals with exogenous IFN during the pregnancy recognition period has been considered as a means to compensate for inadequate secretion of IFN by conceptuses that are delayed in their development and enhance their chances for survival. A series of fertility experiments in sheep with rbIFN indicated increased pregnancy rates (92% vs. 76% [21]; 80% vs. 65% [22]; and 76% vs. 69% [23]). Davis et al. [24] reported a trend toward higher pregnancy rates in rbIFN-treated ewes. Recent evidence indicated that treatment of ewes with exogenous roIFN increased interestrous interval and suppressed oxytocin-induced production of PGF2 [7]. However, administration of rbIFN to cattle actually decreased conception rates by ~10%, probably because of induced hyperthermia and acute decreases in both LH secretion and plasma progesterone [25]. Further, efforts to increase fertility of sheep with IFN have failed given the high percentage of death loss occurring in ewes receiving more than 2 x 107 antiviral units of roIFN (unpublished observations). Indeed, interpretation and comparison of published reports concerning the enhancement of ruminant fertility with exogenous IFN is hampered by failure of authors to indicate the amount of biologically active IFN administered.
The availability of roIFN [26, 27] now permits testing of its effects on fertility, corpus luteum (CL) life span, interactions with endometrial receptors, induction of endometrial protein secretion, and suppression of ER- and OTR-dependent pulsatile secretion of PGF2 (see [28]). Since oIFN is a paracrine hormone secreted by conceptus trophectoderm that acts on uterine epithelium to abrogate the uterine luteolytic mechanism, it is necessary to compare intrauterine (paracrine) versus s.c. (endocrine) injections of roIFN to assess its potential to enhance fertility by suppressing endometrial expression of ER and OTR. The present study tested the hypothesis that antiluteolytic effects of roIFN injected into the uterine lumen (paracrine) or s.c. (endocrine) are equivalent in suppressing expression of ER and OTR and inducing uterine expression of type I IFN regulated genes such as Mx and UCRP.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Mature ewes of primarily Rambouillet breeding were observed daily for estrous behavior using vasectomized rams and were assigned to treatments after exhibiting at least two estrous cycles of normal duration (~16–18 days). All experimental and surgical procedures involving animals complied with the Guide for Care and Use of Laboratory Animals and were approved by the University Laboratory Animal Care and Use Committee of Texas A&M University (Animal Use Protocol AG-239AG).
Experimental Design and Treatments
Sixteen cyclic ewes were fitted with uterine catheters on Day 5 of the estrous cycle (Day 0 = estrus) as described previously [29]. Ewes (n = 4 ewes per treatment) were then allotted randomly to receive intrauterine injections of either control serum proteins (6 mg/day) or roIFN (2 x 107 antiviral units/day), or s.c. injections of saline vehicle (1 ml) or roIFN (2 x 107 antiviral units/day) from Days 11 to 15 postestrus. For intrauterine administration, the uterine horns of each ewe received (0700 and 1900 h) injections of either roIFN (5 x 106 antiviral units/horn/injection) or control serum proteins (equal amount of total protein/horn/injection) twice daily as described previously by Spencer et al. [29]. This regimen of roIFN treatment has been shown to mimic the antiluteolytic effects of the conceptus during the pregnancy recognition period in terms of suppressing endometrial epithelial ER and OTR gene expression and uterine production of luteolytic pulses of PGF2 in response to oxytocin [29]. For s.c. injections, each ewe received (0700 h and 1900 h) injections of either roIFN in saline (1 x 107 antiviral units/injection) or saline vehicle twice daily. All ewes were ovariohysterectomized on Day 16 (see Fig. 1A).
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At hysterectomy, a portion (~1.0 cm) from the middle region of each uterine horn was fixed in fresh 4% paraformaldehyde in PBS (pH 7) for 24 h and embedded in Paraplast-Plus (Oxford Labware, St. Louis, MO). From the remainder of each uterine horn, endometrium was dissected from myometrium, and both tissues were frozen separately in liquid nitrogen and stored at -80°C for RNA extraction. The CL were removed from each ovary, frozen in liquid nitrogen, and stored at -80°C for RNA extraction.
Preparation of Proteins
Recombinant oIFN was produced from a synthetic gene construct in Pichia pastoris and purified at the Fermentation Core Facility, Department of Food Science, University of Nebraska [25, 26]. Intrauterine control and roIFN protein injections were prepared as described previously [29].
RNA Isolation and Analyses
RNA isolation Total cellular RNA was isolated from endometrium and ovarian CL samples using TRIzol reagent (Gibco-BRL, Gaithersburg, MD). The quantity of RNA was assessed spectrophotometrically, and the integrity of RNA was examined by gel electrophoresis in a denaturing 1% agarose gel.
Slot blot hybridization analysis
Steady-state levels of ER mRNA were assessed in endometrial and CL samples using slot blot hybridization analyses. For each ewe, denatured total cellular RNA (20 µg) was analyzed by slot blot hybridization analysis using radiolabeled antisense cRNA probes generated by in vitro transcription with [-32P]UTP (Amersham, Piscataway, NJ) as described previously [29]. Plasmid templates for ovine ER (oER8) [29], ovine Mx [14], ovine OTR [30], bovine UCRP (pKA16) [12], and 18S rRNA (pT718S; Ambion, Austin, TX) were used. The ovine OTR cDNA was kindly provided by Dr. A.P.F. Flint (University of Nottingham, United Kingdom), and the bovine UCRP cDNA was kindly provided by Dr. T.R. Hansen (University of Wyoming). The radioactivity associated with each slot was quantitated by electronic autoradiography using an Instant Imager (Packard, Meriden, CT) and expressed as total counts. The 18S rRNA data were used as a covariate to correct for differences in total RNA loaded.
In Situ Hybridization Analysis
In situ hybridization analysis was performed to localize mRNA in uterine tissues as previously described [13, 29]. Sections were hybridized with radiolabeled antisense or sense cRNA probes generated from linearized plasmid templates, containing oER, oOTR, oMX, or bUCRP cDNAs, using in vitro transcription with [-35S]UTP. Emulsion-coated slides were stored at 4°C for 1 wk, developed in Kodak D-19 developer (Eastman Kodak, Rochester, NY), counterstained with Harris' modified hematoxylin in acetic acid (Fisher, Fairlawn, NJ), coverslipped, and evaluated [29].
Photomicroscopy
Photomicrographs of representative fields of in situ hybridization slides were taken under brightfield and darkfield illumination using a Zeiss Axioplan2 photomicroscope (Thornwood, NY) fitted with a Hamamatsu chilled 3CCD color camera (Hamamatsu Corporation, Bridgewater, NJ). Digital images were captured and assembled using Adobe Photoshop 4.0 (Adobe Systems, Seattle, WA) and a MacIntosh PowerMac G3 computer (Apple Computer, Cupertino, CA). Black-and-white prints were electronically printed using a Kodak DS8650 color printer.
Statistical Analyses
Data were subjected to least-squares ANOVA using General Linear Models (GLM) procedures of the Statistical Analysis System [31]. Slot blot hybridization data for ER, OTR, Mx, and UCRP mRNAs (total counts) were normalized for differences in sample loading using the 18S rRNA data as a covariate in ANOVA. Orthogonal contrasts were used to test effects of treatment [32]. All tests of significance were performed using the appropriate error terms according to the expectation of the mean squares for error. Data are presented as least-squares means with standard errors.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Treatment with roIFN increased (p < 0.01) steady-state levels of endometrial Mx mRNA regardless of route of administration (Fig. 1B), but the increase was greater (p < 0.05) following intrauterine injection of roIFN. In contrast, intrauterine administration of roIFN increased (p < 0.01) steady-state levels of endometrial UCRP mRNA, but s.c. injections did not increase (p > 0.10) UCRP mRNA levels (Fig. 1C).
Only the intrauterine route of injection of roIFN suppressed steady-state levels of ER (p < 0.10) and OTR (p < 0.03) mRNA in the endometrium (Fig. 1, D and E). Subcutaneous injections of roIFN did not affect (p > 0.10) steady-state levels of either endometrial ER and OTR mRNAs.
In Situ Hybridization Analysis of Uterine Mx and UCRP mRNA Expression
In situ hybridization analyses revealed that both routes of roIFN administration increased Mx mRNA abundance in endometrial epithelium and stroma (Fig. 2A). However, intrauterine roIFN induced a much greater increase in Mx mRNA in the glandular epithelium and stroma compared to s.c. injection. These results are consistent with effects of these treatments on steady-state levels of endometrial Mx mRNA.
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Consistent with effects of treatment on endometrial UCRP mRNA levels, intrauterine administration of roIFN specifically increased UCRP mRNA in the luminal epithelium, glandular epithelium, and stroma (Fig. 2B). In the intercaruncular endometrium, intrauterine injections of roIFN increased UCRP mRNA abundance primarily in the subepithelial stroma and glandular epithelium. In the caruncular endometrium, the intrauterine roIFN-induced increase in UCRP mRNA was confined to the subepithelial stroma (data not shown). In some ewes receiving s.c. injections of roIFN, UCRP mRNA abundance was increased slightly in the stroma as compared to the uteri of control ewes. However, the effects of s.c. administered roIFN were variable, with some ewes exhibiting no increase in UCRP mRNA abundance.
In Situ Hybridization Analysis of Uterine ER and OTR mRNA Expression
In controls, ER mRNA was abundant in the endometrial epithelium and stroma (Fig. 3A). Ewes receiving s.c. injections of saline had abundant ER mRNA in both the endometrial epithelia and stroma. In ewes receiving intrauterine injections of roIFN, ER and OTR mRNA were not detected in the endometrial epithelium. However, ER mRNA was detected at a low level in the stroma. Consistent with effects of treatment on epithelial ER mRNA expression, OTR mRNA was abundant in the luminal and superficial glandular epithelium of ewes receiving s.c. saline or roIFN and in ewes receiving intrauterine control proteins (Fig. 3B). However, OTR mRNA was undetectable in the endometrial epithelium of ewes receiving intrauterine injections of roIFN.
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Steady-State Levels of Mx and UCRP mRNA in the Ovarian Corpus Luteum
As illustrated in Figure 4, injections of roIFN increased (p < 0.01) Mx and UCRP mRNA in CL regardless of route of administration.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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(paracrine effect) suppress expression of ER and OTR to abrogate the uterine luteolytic mechanism [2–4] and are the first to clearly demonstrate that exogenous roIFN (s.c., endocrine effect) does not block expression of either ER or OTR. These results may explain why exogenous rbIFN failed to extend interestrous intervals in ewes [21–23, 33], why systemic infusions of conceptus homogenates failed to extend luteal life span [1], and why 4 mg roIFN s.c. daily between Days 11 to 15 is required to extend interestrous intervals to only 22.6 days compared to 16.7 days for control ewes [7]. It has been postulated that supplementation of inseminated ewes with exogenous rbIFN or roIFN could compensate for inadequate secretion of antiluteolytic IFN by conceptuses and prevent luteolysis. In theory, this management strategy would increase survival rates of conceptuses delayed in development and, consequently, pregnancy rates. However, the present study determined that antiluteolytic effects of intrauterine roIFN (paracrine) and s.c roIFN (endocrine) are not equivalent. Therefore, this hypothesis must be rejected.
Treatment of ewes with rbIFN increased pregnancy rates [21–23] or tended to increase pregnancy rates [24]. Although these reports indicate that rbIFN-injected ewes had higher pregnancy rates than ewes injected with placebo, there was no indication of how pregnancy rates for placebo-treated control ewes compared with those for ewes in the respective flocks that were mated but not handled and injected daily. Pregnancy rates for controls (60–76%) in these four studies are lower than the expected pregnancy rates (80–85%) for ewes allowed to mate naturally. Therefore, the claim of increased fertility should be evaluated with some reservation. Exogenous rbIFN may only reduce effects of stress on ewes resulting from daily handling and injections.
Radiolabeled rbIFN [34], rhIFN [17], and oIFN bind ovine endometrial membrane receptors and are displaced equally by unlabeled oIFN, suggesting that these type I IFNs bind to the same receptor with similar affinities and have the potential to elicit similar biological effects. However, intrauterine injections of 667 µg/day rbIFN was required to elicit antiluteolytic effects, whereas intrauterine injections of only 100 µg/day of oIFN was antiluteolytic. Davis et al. [24] reported that intrauterine injections of rhIFN at 100 and 200 µg/day did not affect interestrous intervals, whereas 100 µg/day oIFN extended the interestrous interval in ewes. Differences in interactions between oIFN, rhIFN, and rbIFN, and the type I IFN receptor subunits may contribute to differences in biological activity. Ovine IFN apparently binds to two endometrial membrane receptor populations—one of 100 kDa and another of 70 kDa—whereas rbIFN binds only the 100-kDa receptor [35]. Recent evidence indicates that the endometrium has only one type I IFN receptor, although it consists of two subunits, IFNAR-1 and IFNAR-2 [36]. Differences in signal transduction pathways activated by the various members of the type I IFN family may account for the 6-fold lower antiluteolytic activities of rhIFN or rbIFN. For example, IFN, but not rbIFN, induces GCP-2 expression by cow endometrium [15].
Effects of roIFN on gene expression appear to depend on route of administration. Results of the present study indicate differential effects of roIFN, depending on its delivery into the uterine lumen (antiluteolytic effect) or systemically (no antiluteolytic effect), on induction of type I IFN-regulated genes such as Mx and UCRP mRNA. Intrauterine injections of roIFN strongly enhanced expression of Mx and UCRP. In endometrium of ewes receiving s.c. injections, roIFN induction of Mx was lower as compared to intrauterine injection, and UCRP mRNA levels were unaffected by s.c. roIFN. In regard to route of administration, the endometrial tissue concentration of roIFN is likely to be greater in ewes receiving the intrauterine than in those receiving the s.c. route of administration. Moreover, the nature of IFN induction of Mx and UCRP mRNA in the stroma is not known, but it may be elicited by an interferonomedin produced by epithelial cells and secreted in a basal direction [4]. Also, the signal transduction pathway(s) activated by IFN that regulate Mx gene expression may be substantially different than that for UCRP. This idea is supported by observations that Mx gene expression remains strong in the luminal epithelium of early pregnant ewes [14]. During early pregnancy, UCRP mRNA in the ovine endometrium was first detected in the luminal epithelium on Days 11 and 13 but was not detected in that cell type after Day 13 [13]. However, UCRP mRNA expression increased in the stroma, glands, and myometrium after Day 13.
Initially, CL samples were collected and analyzed to serve as a positive control for effects of exogenous roIFN. The hypothesis was that s.c., but not intrauterine, administration of roIFN would induce expression of type I IFN-responsive genes in the CL. This observation would have supported previous observations that exogenous roIFN extends the interestrous interval by a direct action on the CL [7]. Unexpectedly, intrauterine and s.c. roIFN were equivalent in their ability to increase expression of Mx and UCRP in the CL. Effects of the cycle or pregnancy on Mx and UCRP gene expression in the CL is not known. One explanation is a direct effect of IFN on the CL; however, results of several studies indicated that increased levels of antiviral activity cannot be detected in the peripheral circulation or uterine venous and lymphatic drainage in pregnant ewes (see [2–4] for review). Another explanation is that pregnancy and/or intrauterine administration of roIFN induces substances in the endometrium that have systemic effects on organs, including the ovaries. Finally, roIFN may exert effects on resident uterine blood cells which then affect luteal function. These hypotheses are supported by observations that expression of Mx and UCRP mRNA is up-regulated in the stroma, glands, and myometrium by the conceptus [13, 14] or by intrauterine injections of roIFN (present study). Indeed, the presence of T lymphocytes and macrophages, and production of tumor necrosis factor by macrophages are associated with CL regression, although their role in luteolysis or other aspects of luteal function is not known [37, 38]. The CL secrete a specific chemoattractant for eosinophils, which produce factors that may play a role in CL function [38], and eosinophils in sheep uteri express type I IFN receptors through which IFN could influence function (unpublished observations). Inhibition of leukocyte-mediated lysis of luteal cells may result from rbIFN or roIFN treatment. Results of previous studies have indicated that rbIFN did not alter expected luteal life span in ewes [22]. However, daily i.m. or intrauterine injections of rbIFN (2 mg) extended interestrous intervals by 6 days in cattle [39]. The disparity in these results may be due to the slightly higher amino acid sequence homology between rbIFN and rbIFN (51%) than between rbIFN and roIFN (48%) [35, 36] or to differences among species in responsiveness to type I IFNs. A major difference between IFN (165 or 166 amino acids) and IFN (172 amino acids) is an additional six carboxy-terminal amino acids. Although structural differences do not explain differences in antiluteolytic activity [40], they are expected to explain why GCP-2 is induced in the uterus by only rbIFN [15].
There is considerable evidence that the antiluteolytic effects of oIFN are on the uterine endometrium, particularly the luminal and superficial glandular epithelium. However, results of one study suggest an effect of conceptus secretory products on the CL. Mapletoft et al. [41] anastomosed the main uterine veins from gravid and nongravid uterine horns of unilaterally pregnant ewes having one CL in each ovary, and they found bilateral CL maintenance rather than the expected maintenance of only the ipsilateral CL. They also reported that the CL regressed when the uterine vein ipsilateral to the conceptus received blood only from the nongravid uterine horn. The CL of pregnant ewes are more resistant to doses of exogenous oxytocin and estradiol that cause luteolysis in cyclic ewes; and during maternal recognition of pregnancy, ovarian follicular populations are suppressed on the ovary bearing the CL but not on the contralateral ovary (see [2–4]). Some have suggested that this is due to effects of PGE (see [2–4]). The present results suggest that effects of oIFN may include induction of endocrine effectors that influence the ovary/CL to complement paracrine antiluteolytic effects of oIFN.
Results of the present study clearly indicate differential effects of intrauterine (paracrine) and s.c. (endocrine) roIFN on the uterus but not on the CL. Additional research is necessary to understand the mechanism(s) responsible for these differential effects and factors that account for the systemic effects of roIFN following injection into the uterine lumen. These findings suggest that roIFN administered systemically does not abrogate the luteolytic mechanism and is not likely, therefore, to enhance fertility by overcoming deficiencies in secretion of oIFN by conceptuses that are delayed in their development.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 Correspondence: Fuller W. Bazer, Department of Animal Science and Center for Animal Biotechnology and Genomics, Albert B. Alkek Institute of Biosciences and Technology, 442D Kleberg Center, Texas A&M University, College Station, TX 77843-2471. FAX: 409 862 2662; fbazer{at}cvm.tamu.edu
3 Current address: Animal and Veterinary Science Department, 216 Agricultural Sciences Building, University of Idaho, Moscow, ID 83844-2330.
Accepted: March 11, 1999.
Received: December 29, 1998.
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. J Immunol 1997; 158:4351–4357.[Abstract] genes are coordinately expressed and encode functional polypeptides. Mol Cell Biol 1985; 5:768–779. on fertility in ewes. Theriogenology 1991; 36:231–239. in cows: effects on hyperthermia, luteal cells, metabolism of progesterone, and secretion of LH. J Endocrinol 1992; 133:175–182.[Abstract]This article has been cited by other articles:
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  C.A. Gifford, A.M. Assiri, M.C. Satterfield, T.E. Spencer, and T.L. Ott Receptor Transporter Protein 4 (RTP4) in Endometrium, Ovary, and Peripheral Blood Leukocytes of Pregnant and Cyclic Ewes Biol Reprod, September 1, 2008; 79(3): 518 - 524. [Abstract] [Full Text] [PDF]
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 G. Song, J. Kim, F. W. Bazer, and T. E. Spencer Progesterone and Interferon Tau Regulate Hypoxia-Inducible Factors in the Endometrium of the Ovine Uterus Endocrinology, April 1, 2008; 149(4): 1926 - 1934. [Abstract] [Full Text] [PDF]
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J. F. Oliveira, L. E. Henkes, R. L. Ashley, S. H. Purcell, N. P. Smirnova, D. N. R. Veeramachaneni, R. V. Anthony, and T. R. Hansen Expression of Interferon (IFN)-Stimulated Genes in Extrauterine Tissues during Early Pregnancy in Sheep Is the Consequence of Endocrine IFN-{tau} Release from the Uterine Vein Endocrinology, March 1, 2008; 149(3): 1252 - 1259. [Abstract] [Full Text] [PDF]
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 T. E Spencer, O. Sandra, and E. Wolf Genes involved in conceptus-endometrial interactions in ruminants: insights from reductionism and thoughts on holistic approaches Reproduction, February 1, 2008; 135(2): 165 - 179. [Abstract] [Full Text] [PDF]
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M. C. Satterfield, K. A. Dunlap, K. Hayashi, R. C. Burghardt, T. E. Spencer, and F. W. Bazer Tight and Adherens Junctions in the Ovine Uterus: Differential Regulation by Pregnancy and Progesterone Endocrinology, August 1, 2007; 148(8): 3922 - 3931. [Abstract] [Full Text] [PDF]
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G. Song, F. W Bazer, and T. E Spencer Pregnancy and interferon tau regulate RSAD2 and IFIH1 expression in the ovine uterus Reproduction, January 1, 2007; 133(1): 285 - 295. [Abstract] [Full Text] [PDF]
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 T. R. Bilby, A. Sozzi, M. M. Lopez, F. T. Silvestre, A. D. Ealy, C. R. Staples, and W. W. Thatcher Pregnancy, Bovine Somatotropin, and Dietary n-3 Fatty Acids in Lactating Dairy Cows: I. Ovarian, Conceptus, and Growth Hormone-Insulin-Like Growth Factor System Responses. J Dairy Sci, September 1, 2006; 89(9): 3360 - 3374. [Abstract] [Full Text] [PDF]
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M. H. Melner, A. L. Haas, J. M. Klein, A. R. Brash, W. E. Boeglin, S. K. NagDas, V. P. Winfrey, and G. E. Olson Demonstration of Ubiquitin Thiolester Formation of UBE2Q2 (UBCi), a Novel Ubiquitin-Conjugating Enzyme with Implantation Site-Specific Expression Biol Reprod, September 1, 2006; 75(3): 395 - 406. [Abstract] [Full Text] [PDF]
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G. Song, T. E. Spencer, and F. W. Bazer Progesterone and Interferon-{tau} Regulate Cystatin C in the Endometrium Endocrinology, July 1, 2006; 147(7): 3478 - 3483. [Abstract] [Full Text] [PDF]
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Y. Chen, J. A. Green, E. Antoniou, A. D. Ealy, N. Mathialagan, A. M. Walker, M. P. Avalle, C. S. Rosenfeld, L. B. Hearne, and R. M. Roberts Effect of Interferon-{tau} Administration on Endometrium of Nonpregnant Ewes: A Comparison with Pregnant Ewes Endocrinology, May 1, 2006; 147(5): 2127 - 2137. [Abstract] [Full Text] [PDF]
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G. Song, F. W. Bazer, G. F. Wagner, and T. E. Spencer Stanniocalcin (STC) in the Endometrial Glands of the Ovine Uterus: Regulation by Progesterone and Placental Hormones Biol Reprod, May 1, 2006; 74(5): 913 - 922. [Abstract] [Full Text] [PDF]
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G. Song, T. E. Spencer, and F. W. Bazer Cathepsins in the Ovine Uterus: Regulation by Pregnancy, Progesterone, and Interferon Tau Endocrinology, November 1, 2005; 146(11): 4825 - 4833. [Abstract] [Full Text] [PDF]
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M. H. Melner, N. A. Ducharme, A. R. Brash, V. P. Winfrey, and G. E. Olson Differential Expression of Genes in the Endometrium at Implantation: Upregulation of a Novel Member of the E2 Class of Ubiquitin-Conjugating Enzymes Biol Reprod, February 1, 2004; 70(2): 406 - 414. [Abstract] [Full Text] [PDF]
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S. Kim, Y. Choi, F. W. Bazer, and T. E. Spencer Identification of Genes in the Ovine Endometrium Regulated by Interferon {tau} Independent of Signal Transducer and Activator of Transcription 1 Endocrinology, December 1, 2003; 144(12): 5203 - 5214. [Abstract] [Full Text] [PDF]
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 B. A. Hicks, S. J. Etter, K. G. Carnahan, M. M. Joyce, A. A. Assiri, S. J. Carling, K. Kodali, G. A. Johnson, T. R. Hansen, M. A. Mirando, et al. Expression of the uterine Mx protein in cyclic and pregnant cows, gilts, and mares, J Anim Sci, June 1, 2003; 81(6): 1552 - 1561. [Abstract] [Full Text] [PDF]
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Y. Choi, G. A. Johnson, T. E. Spencer, and F. W. Bazer Pregnancy and Interferon Tau Regulate Major Histocompatibility Complex Class I and {beta}2-Microglobulin Expression in the Ovine Uterus Biol Reprod, May 1, 2003; 68(5): 1703 - 1710. [Abstract] [Full Text] [PDF]
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M. D. Stewart, Y. Choi, G. A. Johnson, L.-y. Yu-Lee, F. W. Bazer, and T. E. Spencer Roles of Stat1, Stat2, and Interferon Regulatory Factor-9 (IRF-9) in Interferon Tau Regulation of IRF-1 Biol Reprod, February 1, 2002; 66(2): 393 - 400. [Abstract] [Full Text] [PDF]
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Y. Choi, G. A. Johnson, R. C. Burghardt, L. R. Berghman, M. M. Joyce, K. M. Taylor, M. David Stewart, F. W. Bazer, and T. E. Spencer Interferon Regulatory Factor-Two Restricts Expression of Interferon-Stimulated Genes to the Endometrial Stroma and Glandular Epithelium of the Ovine Uterus Biol Reprod, October 1, 2001; 65(4): 1038 - 1049. [Abstract] [Full Text] [PDF]
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G. A. Johnson, M. D. Stewart, C. Allison Gray, Y. Choi, R. C. Burghardt, L.-Y. Yu-Lee, F. W. Bazer, and T. E. Spencer Effects of the Estrous Cycle, Pregnancy, and Interferon Tau on 2',5'-Oligoadenylate Synthetase Expression in the Ovine Uterus Biol Reprod, May 1, 2001; 64(5): 1392 - 1399. [Abstract] [Full Text]
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