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Regular Article |
a Center for Animal Biotechnology and Genomics, Department of Animal Science, Texas A&M University, College Station, Texas 77843-2471
b Department of Veterinary Anatomy and Public Health, College of Veterinary Medicine, Texas A&M University, College Station, Texas 77843
c Departments of Medicine, Molecular and Cellular Biology and Immunology, Baylor College of Medicine, Houston, Texas 77030
ABSTRACT
The enzymes which comprise the 2',5'-oligoadenylate synthetase (OAS) family are interferon (IFN) stimulated genes which regulate ribonuclease L antiviral responses and may play additional roles in control of cellular growth and differentiation. This study characterized OAS expression in the endometrium of cyclic and pregnant ewes as well as determined effects of IFN
and progesterone on OAS expression in cyclic or ovariectomized ewes and in endometrial epithelial and stromal cell lines. In cyclic ewes, low levels of OAS protein were detected in the endometrial stroma (S) and glandular epithelium (GE). In early pregnant ewes, OAS expression increased in the S and GE on Day 15. OAS expression in the lumenal epithelium (LE) was not detected in uteri from either cyclic or pregnant ewes. Intrauterine administration of IFN stimulated OAS expression in the S and GE, and this effect of IFN was dependent on progesterone. Ovine endometrial LE, GE, and S cell lines responded to IFN with induction of OAS proteins. In all three cell lines, the 40/46-kDa OAS forms were induced by IFN, whereas the 100-kDa OAS form appeared to be constitutively expressed and not affected by IFN. The 69/71-kDa OAS forms were induced by IFN in the S and GE cell lines, but not in the LE. Collectively, these results indicate that OAS expression in the endometrial S and GE of the early pregnant ovine uterus is directly regulated by IFN from conceptus and requires the presence of progesterone.
conceptus, cytokines, female reproductive tract, gene regulation, hormone action, implantation/early development, pregnancy, uterus
INTRODUCTION
Interferon tau (IFN), the antiluteolytic pregnancy recognition signal in ruminants, is secreted by trophectoderm of ovine conceptuses (embryo and associated membranes) between Days 11 and 23 of pregnancy [1]. IFN possesses antiviral, antiproliferative, and immunomodulatory activities similar to other type I IFNs [2, 3]. In sheep, IFN binds to classical type I IFN receptors on the endometrial luminal (LE) and superficial glandular epithelia (GE) to prevent uterine release of luteolytic pulses of prostaglandin F2
(PGF) by suppressing transcription of epithelial estrogen-receptor alpha (ER) and oxytocin receptor (OTR) genes [1, 4]. IFN induces or increases expression of a number of IFN-stimulated genes (ISGs) in the ruminant endometrium or endometrial cell lines, including signal transducer and activator of transcription (STAT) 1 and 2 [5, 6], ß2-microglobulin [7], IFN regulatory factor one (IRF-1) [5, 6, 8], ISG17/ubiquitin cross-reactive protein (ISG17/UCRP) [5, 6, 9], Mx protein [10], and 2',5' oligoadenylate synthetase (OAS) [11]. Recent evidence indicates that effects of IFN on endometrial gene expression are mediated by an intracellular signal transduction system involving STAT1, STAT2, and IRFs [5, 6, 8].
The mammalian OAS enzymes are crucial to the IFN-induced antiviral response [12]. They catalyze the polymerization of ATP into 2'-5'-linked oligoadenylates, which activate a constitutively expressed latent endonuclease, ribonuclease L (RNAse L), that rapidly cleaves viral and cellular RNA, thereby blocking viral replication and initiating apoptosis in some cell types. The mammalian OAS genes have undergone multiple gene duplication events resulting in three size classes of enzymes: small (40/46-kDa isoforms), intermediate (69/71-kDa isoforms), and large (100 kDa) [13–17]. The biological significance of these multiple OAS forms is unknown, but each has distinct subcellular locations and functional differences in activation requirements and catalytic parameters [15, 18–20]. In addition to control of viral replication, OAS has been implicated in cell growth, differentiation, and apoptosis [21, 22] as well as attenuation of the IFN response in virus-infected cells [23].
Exposure of the ovine uterus to IFN is required for placental lactogen (PL) and growth hormone (GH) to stimulate expression of genes encoding secretory proteins in the endometrial glands [24]. McAveney et al. [25] found that the 42-kDa form of OAS interacts with the intracellular domain of the long form of the human prolactin receptor (PRL-R) and inhibits STAT1-mediated signaling by PRL to the IRF-1 promoter. Given that ovine PL signals via a homodimer of the ovine prolactin receptor (PRL-R) and a heterodimer of ovine PRL-R and GH receptor (GH-R) [26], induction of OAS expression by IFN during pregnancy in the ewe could potentially mediate the effects of PL on the endometrial GE. Mirando et al. [11] demonstrated that OAS enzymatic activity was twofold greater in endometrium from Day 16 pregnant compared with Day 16 cyclic ewes, and could be increased in cyclic ewes by intrauterine administration of native ovine IFN. However, the localization and forms of OAS protein were not assessed in that study. Therefore, objectives of this study were to 1) determine effects of day of the estrous cycle and early pregnancy on spatial alterations in OAS expression in the ovine uterus, 2) test the hypothesis that intrauterine administration of IFN regulates endometrial OAS expression in vivo, and 3) determine the effects of IFN on OAS protein expression in ovine endometrial LE, GE, and stromal (S) cell lines.
MATERIALS AND METHODS
Animals and Experimental Design
Mature ewes of primarily Rambouillet breeding were observed daily for estrus using vasectomized rams. All ewes exhibited at least two estrous cycles of normal duration (
16–18 days). Experimental and surgical procedures involving animals were approved by the Agricultural Animal Care and Use Committee of Texas A&M University (Animal Use Protocols 7-286 and 239AG). At estrus, ewes were assigned randomly to cyclic or pregnant status. Ewes assigned to pregnant status were bred to intact rams at estrus (Day 0).
Study one Fifty-two ewes were assigned randomly to be ovariohysterectomized (n = 4 ewes/day) on Days 1, 3, 5, 7, 9, 11, 13, or 15 of the estrous cycle and Days 11, 13, 15, 17, or 19 of pregnancy (Day 0 = mating) as described previously [27]. Pregnancy was confirmed by the presence of an apparently normal conceptus in the uterine lumen (observed in uterine flushings on Days 11–17).
At hysterectomy, several sections (1.0–1.5 cm) from the middle of each uterine horn were embedded in Tissue-Tek Optimal Cutting Temperature compound (OCT; Miles Inc., Oneonta, NY), frozen in liquid nitrogen vapor, and stored at -80°C. The remaining endometrium was physically dissected from myometrium, frozen in liquid nitrogen, and stored at -80°C for RNA extraction. In monovulatory pregnant ewes, uterine tissue samples were marked as contralateral or ipsilateral to the ovary bearing the corpus luteum. No contralateral uterine samples were used for this study.
Study two
Eight cyclic ewes were fitted with uterine catheters on Day 5 of the estrous cycle (Day 0 = estrus) as described previously [28]. Ewes (n = 4 ewes per treatment) were then allotted randomly to receive intrauterine injections of either control serum proteins (6 mg/day) or recombinant ovine IFN (roIFN; 2 x 107 antiviral units/day) from Days 11 to 15 proestrus. For intrauterine administration, the uterine horns of each ewe received injections of either roIFN (roIFN; 5 x 106 antiviral units per horn per injection) or control serum proteins (CX; equal amount of total protein per horn per injection) twice daily. This regimen of roIFN treatment has been shown to mimic the antiluteolytic effects of the conceptus during the pregnancy recognition period [29]. All ewes were ovariohysterectomized on Day 16. The endometrium was dissected from the myometrium, frozen in liquid nitrogen, and stored at -80°C for RNA extraction.
Study three
As described previously by Johnson et al. [30], 16 cyclic ewes (Day 0 = estrus) were ovariectomized, fitted with uterine catheters, and randomly assigned (n = 4 ewes per treatment) to receive daily intramuscular injections of steroids and intrauterine injections of protein as follows: 1) 50 mg progesterone (P, Days 5–24) and 200 µg CX (ovine serum proteins, Days 11–24); 2) P and 75 mg ZK 137.316 (a progesterone receptor antagonist, Days 11–24) and CX proteins; 3) P and roIFN (2 x 107 antiviral units, Days 11–24); or 4) P and ZK and roIFN. Both uterine horns of each ewe received twice-daily injections of either CX protein (50 µg/horn per injection) or roIFN (5 x 106 antiviral units/horn per injection). Steroids were administered daily in a total volume of 1 ml corn oil vehicle. All ewes were hysterectomized on Day 25, and the uterus was processed as described above for study one and study two.
Study four
Ovine endometrial LE, GE, or S cell monolayer cultures were grown to 60%–70% confluence on 100-mm tissue culture plates, incubated in serum-free medium for 24 h, and then treated with IFN (104 antiviral units/ml) in serum-free medium for 0, 1, 3, 6, 12, 24, or 48 h. This experiment was repeated a minimum of three times.
Preparation of Proteins
Recombinant ovine IFN was produced from a synthetic gene construct in Pichia pastoris and purified at the Fermentation Core Facility, Department of Food Science, University of Nebraska, as described previously [31]. 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 using Trizol reagent (Life Technologies, Rockville, MD). The quantity of RNA was assessed spectrophotometrically, and integrity of RNA examined by gel electrophoresis in a denaturing 1% agarose gel.
Slot blot hybridization analysis Steady state levels of OAS mRNA were assessed by slot blot hybridization using methods described previously [29]. Denatured total endometrial RNA (20 µg) from each ewe was analyzed using a radiolabeled antisense human 42-kDa OAS cRNA probe. To correct for variation in total RNA loading, a duplicate RNA slot membrane was hybridized with radiolabeled antisense 18S rRNA cRNA (pT718S; Ambion, Austin, TX). Following washing, nonspecific hybridization was removed by RNAse A digestion [32]. The radioactivity associated with each slot was quantitated by electronic autoradiography using an Instant Imager (Packard Instrument Company, Meridian, CT) and is expressed as total counts (TCs).
Immunocytochemical Analysis
Frozen sections (4–8 µm) of uterine tissues embedded in OCT compound in studies 1 and 3 were cut with a cryostat and mounted on Superfrost/Plus microscope slides (Fisher Scientific, Pittsburgh, PA). Sections were fixed in -20°C methanol for 10 min, permeabilized with 0.3% Tween-20 in 0.02 M PBS, and then blocked in antibody dilution buffer (two parts 0.02 M PBS, 1.0% BSA, 0.3% Tween-20 pH 8.0, and one part glycerol) containing 5% normal goat serum for 1 h at room temperature. Sections were rinsed in PBS and incubated overnight at 4°C with 20 µg/ml rabbit anti-human OAS immunoglobulin G (IgG) [15] or 20 µg/ml normal rabbit IgG (Sigma Chemical Company, St. Louis, MO) as a control. Following three rinses in PBS for 10 min each, sections were incubated with fluorescein-conjugated goat anti-rabbit IgG (Zymed, San Francisco, CA) for 1 h at room temperature and again washed in PBS three times for 10 min each. Sections were then overlaid with a coverslip and Prolong Antifade mounting reagent (Molecular Probes, Eugene, OR).
Photomicroscopy and Digital Imaging
Images of representative fields of immunoflourescence slides were recorded using a Zeiss Axioplan2 microscope (Carl Zeiss, Thornwood, NY) fitted with a Hamamatsu C-5810 chilled 3-color CCD camera (Hamamatsu Corporation, Bridgewater, NJ). Digital images were captured, assembled, or both 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.
Cell Culture and Reagents
Immortalized ovine uterine endometrial LE, GE, and S cell lines [5] were maintained in Dulbecco modified Eagle medium with F-12 salts (DMEM-F12; Sigma) supplemented with 10% fetal bovine serum and antibiotics. Whole-cell proteins were extracted as described previously [5, 6]. The protein concentration was determined by Bradford assay (Bio-Rad Laboratories, Burlingame, CA) using BSA as the standard.
Western Blot Analyses
Twenty micrograms of whole-cell extract protein from each sample was separated by SDS-PAGE, transferred to nitrocellulose, and blocked with 5% nonfat milk-TBST (Tris-buffered saline, 0.1% Tween-20) as described previously [27]. Blots were incubated with rabbit anti-human OAS IgG (1:500) as primary antibody in 2% milk-TBST overnight at 4°C, rinsed for 30 min at room temperature with TBST, incubated with peroxidase-conjugated secondary antibody for 1 h at room temperature, and then rinsed again for 30 min at room temperature with TBST. The rabbit anti-human OAS IgG recognizes all five known forms of the OAS protein [15]. Immunoreactive proteins were detected using enhanced chemiluminescence (Amersham/Pharmacia) according to the manufacturer's recommendations.
Statistical Analyses
Data from slot blot hybridization analyses were subjected to least-squares ANOVA (LS-ANOVA) using the General Linear Models procedures of the Statistical Analysis System [33]. Slot blot hybridization data for OAS mRNA (total counts) were normalized for differences in sample loading using the 18S rRNA data as a covariate in ANOVA. Data from study two were subjected to one-way LS-ANOVA. Data from study three were analyzed using preplanned orthogonal contrasts (P + CX vs. P + IFN; P + CX vs. P + ZK + CX; P + IFN vs. P + ZK + IFN) to detect effects of treatment. All tests of significance were performed using the appropriate error terms according to the expectation of the mean squares for error [34]. Data are presented as least-square means TC with standard errors of the mean (SEM).
RESULTS
Effects of the Estrous Cycle and Pregnancy on OAS Expression in Ovine Endometrium
During the estrous cycle (Fig. 1), immunoreactive OAS protein was not detected in the LE by immunofluorescence analyses. In contrast, low amounts of OAS protein were detected in the endometrial S and GE of cyclic ewes. In S, OAS protein was expressed at relatively higher levels in the stratum compactum and appeared to increase slightly between Days 5 and 15. OAS protein was detected in the apical portion of GE in endometrium of all cyclic ewes, but the level of expression did not change.
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During early pregnancy (Fig. 1), OAS protein expression was not different in the endometrium of pregnant and cyclic ewes on Days 11 and 13. However, OAS protein expression appeared to increase in endometrial S and GE of Day 15 pregnant ewes. This increase in S and GE OAS protein expression appeared to be maintained on Day 17, but declined on Day 19.
Intrauterine Administration of Recombinant Ovine IFN Enhances OAS Expression in Ovine Endometrium
As illustrated in Figure 2A, intrauterine administration of roIFN into cyclic ewes elicited an approximately fivefold increase (P < 0.01, CX vs. IFN) in steady-state levels of endometrial OAS mRNA on Day 16. As illustrated in Figure 2B, intrauterine administration of roIFN increased OAS mRNA approximately sixfold in the endometrium of ovariectomized, P-treated ewes (P + CX vs. P + IFN, P < 0.01). Treatment of ovariectomized, P-treated ewes receiving CX proteins with ZK did not affect OAS mRNA expression (P + CX vs. P + ZK + CX, P > 0.10). However, administration of ZK to ewes receiving roIFN ablated IFN stimulation of OAS mRNA expression in the endometrium (P + IFN vs. P + ZK + IFN, P < 0.03).
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Immunofluorescence analyses detected immunoreactive OAS protein in the endometrial S and GE, but not LE of endometrium from ewes in study three (Fig. 3). Treatment with ZK did not appear to affect OAS expression in endometrial S and GE of ovariectomized, P-treated ewes receiving control proteins. IFN appeared to increase expression of OAS in the stratum compactum and spongiosum layers of the S, and in GE, albeit to a lesser extent. In contrast, administration of ZK inhibited roIFN-enhanced OAS expression in endometrial S and GE.
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Effects of Recombinant Ovine IFN on OAS Expression in Ovine Endometrial Cell Lines
In the LE cells, treatment with IFN appeared to slightly increase expression of the 100-kDa OAS form and induce expression of the 40/46-kDa forms of OAS by 6 h of treatment (Fig. 4). In the GE cells, IFN did not appear to increase the expression of the 100-kDa OAS form. However, treatment with IFN did induce expression of the 40/46-kDa and 69/71-kDa forms of OAS within 3 h and 12 h of treatment, respectively. In the S cells, IFN increased expression of the 100-kDa OAS form and induced expression of the 40/46-kDa and 69/71-kDa forms of OAS within 6 h and 12 h of treatment, respectively.
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DISCUSSION
This is the first report of temporal and spatial alterations in OAS protein expression in the ovine uterus. Studies presented here confirm and extend previous studies that OAS expression is directly regulated by IFN in the endometrium of the ovine and bovine uterus [11, 35, 36]. As in the cow [36], expression of OAS in the ovine endometrial S and GE is coordinate with production of IFN by the conceptus [37]. Intrauterine infusion of cyclic ewes with roIFN increased OAS expression in endometrial S and GE. This pattern of expression is similar to that described for other type I ISGs, including Mx and ISG17/UCRP in the ovine uterus during early pregnancy and in cyclic ewes infused with IFN [9, 10, 30]. In pregnant as well as in IFN-treated ewes, OAS increased dramatically in S and GE. Because IFN is not detected in venous or lymphatic drainage [38], it has been assumed that access of IFN to receptors is limited to the endometrial LE and shallow GE. The observation that ISGs are induced in the underlying stroma has led to the hypothesis that LE and perhaps GE produce an "interferonomedin" from the basolateral epithelial surface that acts as a paracrine stimulator of IFN responses in stroma [1]. Another potential explanation for stromal OAS expression is that IFN produced by the conceptus may be transported across the LE cell layer to the uterine stroma. Guillomot and coworkers [39, 40] observed that injection of horseradish peroxidase into the uterine lumen of pregnant ewes and cows resulted in accumulation of the tracer in the intracellular spaces beneath the basement membrane in the stroma. This transport was mediated via both transepithelial endocytotic activity (vesicles) and passage through intercellular spaces around tight junctions. These phenomena were especially marked when circulating progesterone concentrations were high.
In the ovine uterus, neither OAS nor ISG17/UCRP was detectable in LE on Days 13–19 of early pregnancy [9]. The absence of these ISGs in the LE may be due to IFN stimulation of a specific repressor or repressors that inhibits transcriptional activity of IFN-regulated genes [1]. The endometrial LE and superficial GE express IRF-2, a well-characterized negative regulator of ISG expression [8]. In vivo evidence supports the hypothesis that the lack of ISG expression in endometrial LE and superficial GE is due to IFN-regulated repressor proteins such as IRF-2. The paradoxical ability of IFN to increase ISG expression in the ovine endometrial LE cell line in vitro remains unexplained. The LE cell line may lack one or more transcription factors required for IFN to exert negative effects, or these cells may require cell-cell interactions with the stroma to express a true differentiated phenotype and functions observed in vivo.
Results from the present study extend our recent findings that progesterone is required for or permissive to effects of IFN on the ovine endometrium [30, 41]. As expected, administration of roIFN to progesterone-treated ovariectomized ewes induced expression of OAS mRNA and protein within endometrial tissues. However, administration of ZK137.316, a progesterone receptor (PR) antagonist, abolished the ability of roIFN to induce OAS expression above levels for control ewes. Similar results have been reported for the uterine expression of IFN-induced ISG17/UCRP [30], but this is the first report to indicate ovarian steroid-dependent regulation of OAS induction by a type I IFN in any species. The pathway by which progesterone regulates IFN induction of OAS in the ovine endometrium is unknown. In general, progesterone actions in target tissues are poorly understood, and their elucidation is complicated by possible direct and indirect effects of progesterone on endometrial cells. Direct interaction of PR with the OAS gene promoter is unlikely, because OAS expression in the endometrial S and GE during the estrous cycle does not correlate with cell-specific changes in PR gene expression or circulating concentrations of progesterone [42].
In response to conceptus-derived IFN, the progesterone-stimulated uterus expresses OAS proteins in S and GE during the period of pregnancy recognition. Studies utilizing ovine endometrial cell lines demonstrated the constitutive presence of the 100-kDa OAS form and differential effects of ovine IFN on induction of the other two major OAS forms (40/46- and 69/71-kDa forms). In LE, GE, and S cells, IFN induced the 40/46-kDa OAS isoforms, whereas the 69/71-kDa isoforms were induced by IFN only in the GE and S cells. The timing of this induction by IFN is consistent with IFN activation of the IFN-stimulated gene factor 3 (ISGF3) and IRF signaling pathways [6]. Because the three major OAS forms are generated from independent genes, it is likely that each OAS gene has different response elements in its promoter, which may account for the differential effects of types I and II IFNs on OAS gene transcription [12–15]. The differential induction of the 69/71-kDa OAS isoforms in the ovine endometrial epithelial cell lines provides biochemical evidence that GE cells possess a distinct phenotype compared with LE cells. In pregnant ewes and in cyclic ewes receiving intrauterine injections of IFN, OAS expression was clearly increased only in endometrial GE and S cells. Given that IFN induces the 40/46- and 69/71-kDa isoforms in GE and S cell lines, these OAS forms are likely to have a physiological role in IFN actions on the endometrium during early pregnancy in sheep. The precise role of endometrial OAS in the establishment of pregnancy in ruminants is unknown. The OAS system is implicated in the antiviral response and regulation of ISG expression in response to IFNs or viral infection as well as cell growth, differentiation, and apoptosis [12, 21–23]. Each of these OAS-mediated cellular events could contribute to endometrial function during establishment of pregnancy in ruminants [1, 3].
An attractive hypothesis is that the IFN-regulated OAS proteins play a role in the hormonal servomechanism that regulates endometrial GE secretory gene expression during pregnancy. Recently, McAveney et al. [25] identified OAS as a protein that interacts with the long form of the human PRL-R and demonstrated that OAS preferentially modulates the signal transduction pathway of PRL toward activation of genes associated with differentiated function rather than proliferation. Ovine PL signals via a homodimer of the ovine PRL-R as well as a heterodimer of ovine PRL-R and GH-R [26]. Endometrial GE express both PRL-R and GH-R during early pregnancy in sheep [43–45]. In the ovine uterus, Spencer et al. [24] found that exposure of the progesterone-stimulated endometrium to IFN is required for ovine PL and ovine GH to stimulate production of genes encoding secretory proteins, including uterine milk protein (UTMP) and osteopontin (OPN), which are exclusively expressed by endometrial GE. The mononuclear cells of the ovine conceptus trophectoderm express IFN as early as Day 11, but ovine PL is not expressed until Day 16, when differentiation of binucleate trophectoderm cells occurs [37, 46]. Expression of the UTMP gene, the major secretory product of the endometrial GE during pregnancy, is not detected in endometrial GE until Day 17 of pregnancy [44]. Similarly, maximal expression of OPN in GE is not until Day 19 of early pregnancy [47]. The correlated ontogeny of placental IFN and PL production and onset of expression of OAS by GE followed by UTMP and OPN expression lends support to the concept that OAS modifies the signal transduction pathway activated by PL and perhaps GH within the endometrial GE. This hypothesis will be the subject of future investigations into the role of OAS in regulation of endometrial cell functions during early pregnancy in the sheep.
ACKNOWLEDGMENTS
The authors thank Mr. Todd Taylor and Dr. Shawn W. Ramsey of the Texas A&M University Sheep and Goat Center for assistance with animal husbandry, Dr. Kristoff Chwalisz (Schering, AG, Berlin, Germany) for generously providing the ZK136.317 progesterone receptor antagonist, and Dr. Ganes Sen (Cleveland Clinic Foundation, Cleveland, OH) for kindly providing the human OAS cDNA.
FOOTNOTES
First decision: 16 October 2000.
1 Supported by grant HD32534 from the National Institutes of Health (NIH) to F.W.B. and T.E.S., BARD grant US-2643-95 to F.W.B., U.S. Department of Agriculture-NRICGP grant 95-37203-2185 to F.W.B. and R.C.B., and in part by NIH grants P30 ES09106 and 1-F32-HD08501 to G.A.J. 
2 Correspondence: Thomas E. Spencer, Center for Animal Biotechnology and Genomics, 442 Kleberg Center, 2471 TAMU, Texas A&M University, College Station, TX 77843-2471. FAX: 979 862 2662; tspencer{at}ansc.tamu.edu
Accepted: December 13, 2000.
Received: August 28, 2000.
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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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C. S. Rosenfeld, C.-S. Han, A. P. Alexenko, T. E. Spencer, and R. M. Roberts Expression of Interferon Receptor Subunits, IFNAR1 and IFNAR2, in the Ovine Uterus Biol Reprod, September 1, 2002; 67(3): 847 - 853. [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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 L.-Y. Yu-Lee Prolactin Modulation of Immune and Inflammatory Responses Recent Prog. Horm. Res., January 1, 2002; 57(1): 435 - 455. [Abstract] [Full Text] [PDF]
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