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RESEARCH |
Center for Animal Biotechnology and Genomics and Department of Animal Science, Texas A&M University, 442 Kleberg Center, 2471 TAMU, College Station, Texas 77843-2471, USA
Correspondence should be addressed to T E Spencer; Email: tspencer{at}tamu.edu
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionAcknowledgementsReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionAcknowledgementsReferences |
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Recent transcriptional profiling experiments identified RSAD2 and IFIH1 as genes induced by IFNT from the conceptus in ovine and bovine endometria during early pregnancy (Gray et al. 2006, Klein et al. 2006). Radical S-adenosyl methionine domain containing 2 (RSAD2; alias viperin) is a cytoplasmic antiviral protein induced by Type I IFNs that can inhibit infection of cells with human cytomegalovirus (Chin & Cresswell 2001). Interferon-induced with helicase C domain 1 (IFIH1; alias MDA5) is a RNA helicase that through its ATP-dependent unwinding of RNA, promotes mRNA degradation by specific RNases and is involved in innate immune defense against viruses as well as cellular growth suppression (Kang et al. 2002, 2004). IFIH1 senses intracellular viral infection and triggers innate antiviral responses including the production of Type I IFNs (Yoneyama et al. 2005). Both RSAD2 and IFIH1 are produced during a viral infection in response to IFNs to limit viral replication and modulate subsequent adaptive immunity (Katze et al. 2002, Helbig et al. 2005). Similar to other Type I IFNs, IFNT elicits antiviral, antiproliferative, and immunomodulatory activities in homologous and heterologous cells (Pontzer et al. 1991, Alexenko et al. 1997, Khan et al. 1998, Johnson et al. 1999a, 1999b, 1999c, 1999d, 1999e). 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 & Hansen 2002, Croy et al. 2003b).
Although RSAD2 and IFIH1 have been identified as pregnancy- and IFNT-stimulated genes in the ovine uterine endometrium, the temporal and spatial alterations in their expression in the endometrium during early pregnancy and in response to P4 and IFNThave not been investigated. Our working hypothesis that RSAD2 and IFIH1 are induced in the endometrium in a cell-type specific manner by IFNT from the conceptus during early pregnancy and have biological roles in establishing uterine receptivity to implantation by the conceptus. As first step in testing this hypothesis, studies were conducted to determine effects of: (1) stage of the estrous cycle and early pregnancy on RSAD2 and IFIH1 expression in the ovine uterus; (2) P4 and IFNT on RSAD2 and IFIH1 expression in the ovine uterus; and (3) IFNT on RSAD2 and IFIH1 expression in ruminant endometrial cell lines.
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Experimental design
Study 1
At estrus (day 0), ewes were mated to either an intact or vasectomized ram as described previously (Spencer et al. 1999a) and then hysterectomized (n=5 ewes/day) on day 10, 12, 14, or 16 of the estrous cycle or day 10, 12, 14, 16, 18, or 20 of pregnancy. To confirm the pregnancy status, the uterine lumen was flushed with saline on days 10–16 of pregnancy and examined for the presence of a morphologically normal conceptus(es). At hysterectomy, several sections (~0.5 cm) from the mid-portion of each uterine horn ipsilateral to the corpus luteum were fixed in fresh 4% paraformaldehyde in PBS (pH 7.2). After 24 h, fixed tissues were changed to 70% ethanol for 24 h and then dehydrated and embedded in Paraplast-Plus (Oxford Labware, St. Louis, MO, USA). Several sections (1–1.5 cm) from the middle of each uterine horn were embedded in Tissue-Tek OCT compound (Miles, Oneonta, NY, USA), 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 subsequent RNA extraction. In monovulatory pregnant ewes, uterine tissue samples were marked as either contralateral or ipsilateral to the ovary bearing the corpus luteum; no tissues from the contralateral uterine horn were used for this study.
Study 2
Sixteen cyclic ewes were ovariectomized and fitted with intrauterine (IU) catheters on day 5 post-estrus as described previously (Gray et al. 2006) and injected daily i.m. with 75 mg P4 between days 5 and 16. Ewes were then assigned randomly (n=5 ewes/treatment) to receive one of the following treatment regimens between days 11 and 16: (1) P4 and daily IU infusions of control serum proteins (P4 + CX); (2) P4 and 75 mg of ZK136,317 (Schering, Berlin, Germany), a progesterone receptor (PGR) antagonist and CX proteins (P4 + ZK + CX); (3) P4 and IU IFNT (2 x 107 antiviral units) (P4 + IFN); or (4) P4 and ZK and IU IFNT (P4 + ZK + IFN). The P4 and ZK were administered daily in corn oil vehicle. Both uterine horns of each ewe received twice daily injections of either CX proteins (50 µg/horn per injection) or recombinant ovine IFNT (5 x 106 antiviral units/horn per injection with CX proteins). Recombinant ovine IFNTwas produced in Pichia pastoris and purified as described previously (Van Heeke et al. 1996). 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, Johnson et al. 2001, Kim et al. 2003). All ewes were hysterectomized on day 17. The uterus was processed for histology and the endometrium obtained for RNA extraction as described in Study 1.
Cell culture
Immortalized ovine uterine endometrial LE cells were cultured as described previously (Johnson et al. 1999c). Bovine endometrial (BEND) cells (Johnson et al. 1999a) were kindly provided by Dr Thomas R Hansen (Colorado State University, Fort Collins, CO, USA). Ovine LE and BEND cells were maintained in 150 mm culture dishes containing DMEM (Dulbecco’s modified essential medium) with F-12 salts (DMEM-F12; Sigma-Aldrich Corp.) supplemented with 5% serum and antibiotics. When cells reached 70–80% confluency, they were treated with either IFNT (2 x 107 antiviral unit (AVU)/ml) or left untreated as a control for 24 h in serum-free medium. The experiment was independently repeated three times in each cell type.
RNA isolation
Total cellular RNA was isolated from frozen endometrium or cultured cells using the Trizol reagent (Gibco-BRL) according to manufacturer’s recommendations. The quantity and quality of total RNA was determined by spectrometry and denaturing agarose gel electrophoresis respectively.
Cloning of partial cDNAs for ovine RSAD2 and IFIH1
Partial cDNAs for ovine RSAD2 and IFIH1 mRNAs were amplified by RT-PCR using total RNA endometrial tissues from day 18 of pregnancy using specific primers based on human RSAD2 mRNA (Genbank NM_080657
[GenBank]
; forward, 5'-GAG GCC AAG AAA GGT CTG C-3'; reverse, 5'-CCAAGA ACG CTT CAA ACT CC-3') and human IFIH1 mRNA (Genbank AF095844
[GenBank]
; forward, 5'-TTC CGC AAA GAG TTC AAA CC-3'; reverse, 5'-AAT GTG TTC TTC GGG TTT GG-3'). The RT of cellular total RNA into cDNA was performed, as described previously (Stewart et al. 2000). The PCR amplification was conducted as follows for RSAD2 and IFIH1: (1) 95 °C for 5 min; (2) 95 °C for 30 s, 56.5 °C for 40 s (for RSAD2), 57 °C for 40 s (for IFIH1), and 72 °C for 1 min for 35 cycles; and (3) 72 °C for 10 min. The partial cDNAs for ovine RSAD2 and IFIH1 PCR products were cloned into pCRII using a T/A Cloning Kit (Invitrogen) and their sequences verified using an ABI PRISM Dye Terminator Cycle Sequencing Kit and ABI PRISM automated DNA sequencer (Perkin-Elmer Applied Biosystems, Foster City, CA, USA).
Slot blot hybridization analyses
Steady-state levels of mRNA in ovine endometrium were assessed by slot blot hybridization as described previously (Spencer et al. 1999c, Choi et al. 2001a). For RSAD2 and IFIH1 antisense cRNA probes, the plasmids were linearized with XbaI and in vitro transcription was conducted with SP6 RNA polymerase. Sense cRNA probes were generated using BamHI and T7 RNA polymerase. Radiolabeled antisense and sense cRNA probes were then generated by in vitro transcription with [
-32P]-UTP. Denatured total endometrial RNA (20 µg) from each ewe was hybridized with radiolabeled cRNA probes. To correct for variation in total RNA loading, a duplicate RNA slot membrane was hybridized with radiolabeled antisense 18S cRNA (pT718S; Ambion, Austin, TX, USA). Following washing, the blots were digested with RNase A and radioactivity associated with slots quantified using a Typhoon 8600 MultiImager (Molecular Dynamics, Piscataway, NJ, USA).
Semiquantitative RT-PCR analysis
RSAD2 and IFIH1 mRNA levels in immortalized ovine endometrial LE and BEND cells were assessed using semi-quantitative RT-PCR as described previously (Stewart et al. 2000). Briefly, isolated total cellular RNA was treated with RQ1 RNase Free-DNase1 (Promega) and then ethanol-precipitated. The cDNA was synthesized from total cellular RNA (5 µg) isolated from both cell-lines using random and oligo (dT) primers and SuperScript II Reverse Transcriptase (Life Technologies). Newly synthesized cDNA was acid-ethanol precipitated, resuspended in 20 µl sterile water, and stored at –20 °C. The cDNAs were diluted (1:10) in sterile water before use in PCR. The primers, PCR amplification and verification of their sequences were conducted as described in the section on cloning partial cDNAs. Housekeeping ß-actin (ACTB) primers were forward (5'-ATGAAGATCCTCACGGAACG-3') and reverse (5'-GAAGGTGGTCTCGTGAATGC-3'), which amplified a 270-bp product. PCR amplification was conducted as follows for ACTB: (1) 95 °C for 5 min; (2) 95 °C for 30 s, 57°C for 30 s, and 72 °C for 1 min for 25 cycles; and (3) 72 °C for 10 min. After PCR, equal amounts of reaction product were analyzed using a 1.5% agarose gel, and PCR products were visualized using ethidium bromide staining. The amount of DNA present was quantified by measuring the intensity of light emitted from correctly sized bands under u.v. light using a ChemiDoc EQ system and Quantity One software (Bio-Rad).
In situ hybridization analyses
Location of mRNA expression in uterine sections (5 µm) was determined by radioactive in situ hybridization analysis as described previously (Spencer et al. 1999c, Choi et al. 2001a). Briefly, deparaffinized, rehydrated and deproteinated uterine tissue sections were hybridized with radiolabeled antisense or sense cRNA probes generated from linearized RSAD2 and IFIH1 partial cDNAs using in vitro transcription with [-35S]-UTP. After hybridization, washing, and RNase A digestion slides were dipped in NTB-2 liquid photographic emulsion (Kodak), and exposed at 4 °C for 1–2 weeks. Slides were developed in Kodak D-19 developer, counterstained with Gill’s hematoxylin (Fisher Scientific, Fairlawn, NJ, USA), and then dehydrated through a graded series of alcohol to xylene. Coverslips were then affixed with Permount (Fisher). Images of representative fields were recorded under brightfield or darkfield illumination using a Nikon Eclipse 1000 photomicroscope (Nikon Instruments Inc., Lewisville, TX, USA) fitted with a Nikon DXM1200 digital camera.
Statistical analyses
All quantitative data were subjected to least-squares analyses of variance (ANOVA) using the Statistical Analysis System (SAS Institute, Cary, NC, USA). Slot blot hybridization data were corrected for differences in sample loading using the 18S rRNA data as a covariate. Data from Study 1 were analyzed for effects of day, pregnancy status (cyclic or pregnant), and their interaction. Data from Study 2 were analyzed using orthogonal contrasts (P4 + CX vs P4 + IFN; P4 + ZK + CX vs P4 + ZK + IFN; and P4 + CX vs P4 + ZK + CX) to elucidate effects of treatment. Semi-quantitative RT-PCR data was analyzed using the ACTB data as a covariate. All tests of significance were performed using the appropriate error terms according to the expectation of the mean squares for error. A P-value of 0.05 or less was considered significant. Data are presented as least-square means (LSM) with standard errors (S.E.).
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). In contrast, RSAD2 mRNA increased (P<0.01, quadratic) about sixfold between days 12 and 16 and was maintained through day 20 in pregnant ewes. Similarly, IFIH1 mRNA increased (P<0.01, quadratic) about 2.5-fold between days 12 and 16. The presence of a conceptus increased endometrial RSAD2 and IFIH1 mRNA between days 10 and 16 (P<0.01, day x status; Fig. 1).
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) and IFIH1 (Fig. 3) mRNAs in uteri of cyclic and pregnant ewes. RSAD2 mRNA was low and not different between uteri from day 10 cyclic and pregnant ewes (Fig. 2). Between days 10 and 12 of pregnancy, RSAD2 mRNA increased in the middle glands and to a lower extent in the stratum compactum stroma. Between days 14 and 20 of pregnancy, RSAD2 mRNA was present predominantly in the endometrial glands, and stroma and immune cells, but not in LE, sGE, myometrium, or conceptus trophectoderm. Interestingly, RSAD2 mRNA declined in the endometrial glands after day 16 of pregnancy. Similar to RSAD2, IFIH1 mRNA was low and not different between uteri from day 10 cyclic and pregnant ewes (Fig. 3). Between days 10 and 12 of pregnancy, IFIH1 mRNA increased slightly in the middle glands and stratum compactum stroma. Between days 14 and 18 of pregnancy, IFIH1 mRNA was present predominantly in the stratum compactum stroma of the endometrium, middle glands, and immune cells, and not observed in the endometrial LE, sGE, myometrium, or conceptus trophectoderm. The melanocytes underneath the LE do not have IFIH1 mRNA, but appear white in darkfield photomicrographs. Between days 18 and 20, IFIH1 mRNA abundance declined in the endometrial stroma. The presence of RSAD2 and IFIH1 mRNAs in immune cells within the endometrium was based on visual observations of cell morphology.
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). Treatment of ewes with the ZK 136,317 PGR antagonist did not affect (P>0.10, P4 + CX vs P4 + ZK + CX) endometrial RSAD2 or IFIH1 mRNA abundance (Fig. 4B). For ewes receiving P4 alone, IU recombinant ovine IFNT increased (P<0.001) steady-state levels of RSAD2 and IFIH1 mRNAs 10-fold and 8.3-fold respectively, in the endometria (P<0.001, P4 + CX vs P4 + IFN; Figs 4B and 5A). Similarly, for ewes receiving P4 + ZK treatment, IU recombinant ovine IFNT increased RSAD2 and IFIH1 mRNAs in the endometrium about 9.3-fold and 5.6-fold respectively (P<0.001, P4 + ZK + CX vs P4 + ZK + IFN).
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and 5B). Similar to day 16–18 pregnant ewes, RSAD2 and IFIH1 mRNA were increased by IFNT primarily in the endometrial stroma and immune cells and, to a lower extent, in the endometrial glands of uteri from ewes receiving P4 + IFNT treatment. In P4 + ZK ewes, IFNT increased RSAD2 and IFIH1 mRNA in the endometrial stroma and immune cells. Further, IFNT increased IFIH1 mRNA in endometrial LE of ewes receiving P4 + ZK treatment (Fig. 5B).
Effects of IFNTon RSAD2 and IFIH1 in endometrial cells
In untreated ovine endometrial LE (oLE) and BEND cells maintained in serum-free medium, IFIH1 but not RSAD2 mRNA was detected (Fig. 6). Treatment of both oLE and BEND cells with recombinant ovine IFNT increased (P<0.0001) RSAD2 and IFIH1 mRNA levels.
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In the ovine uterus, induction of RSAD2 and IFIH1 mRNA by the presence of the conceptus during pregnancy and by IFNT was limited to endometrial stroma and middle to deep glands, as well as resident immune cells based on visual observations of cell morphology. The majority of ISGs induced by IFNT without a requirement for P4 in the ovine uterus are restricted to endometrial stroma and middle to deep glands as well as immune cells (see (Spencer et al. 2004a, 2004c) for review). A variety of ruminant and human cell lines have been used to determine that IFNT activates the classical JAK-STAT-IFN regulatory factor (IRF) signaling pathway utilized by other Type I IFNs that involves ISGF3 (STAT1, STAT2, ISGF3G complex), GAF (gamma activated unit) (STAT1 dimer), and IRF one (IRF1; see Stark et al. 1998, Spencer et al. 2004c). ISGF3 transactivates genes through binding an IFN-stimulated response element (ISRE), whereas GAF binds to a gamma activation sequence element in genes such as IRF1. Further, IRF1 transactivates genes through an IRF element (IRFE). Similar to findings for RSAD2 and IFIH1 in the present study, results of in vivo studies indicate that many classical IFN-stimulated genes (STAT1, STAT2, IRF1, ISGF3G, GBP2, IFI6, IFI56, ISG15, MIC, B2M, OAS) are not induced or increased by IFNT in LE and sGE of the sheep uterus (Johnson et al. 1999d, 2001, Choi et al. 2001b, 2003, Kim et al. 2003). This finding was initially surprising because all ovine endometrial cell types express IFNAR1 and IFNAR2 subunits of the common Type I IFN receptor (Rosenfeld et al. 2002). However, available results also indicate that IRF2, a potent transcriptional repressor of IFN-stimulated genes (Mamane et al. 1999), is expressed specifically in endometrial LE and sGE and represses transcriptional activity of promoters containing ISRE or IRFE (Choi et al. 2001b). Thus, IRF2 in LE and sGE is proposed to restrict IFNT induction of many IFN-stimulated genes to endometrial stroma and glandular epithelium. In fact, all components of ISGF3 (STAT1, STAT2, ISGF3G) and other studied IFN-stimulated genes (B2M, GBP2, G1P2, ISG15, G1P3, IFI56, MIC, OAS) contain ISREs in their promoters. Further, the promoter regions of the human and fish RSAD2 genes contain multiple IRFEs (Chin & Cresswell 2001, Sun & Nie 2004). Similarly, the promoter region of the human IFIH1 gene has predicted ISRE and IRFE (unpublished results). Thus, the constitutive presence and pregnancy-specific increase in IRF2 in ovine endometrial LE/sGE in vivo is proposed to prevent IFNT induction of RSAD2 and IFIH1 in those epithelia. P4 appears to be involved in this cell-type specification of IFNT actions, because IFNT induced IFIH1 mRNA in the LE of the endometrium in P + ZK-treated ewes in the present study. Immortalized ovine endometrial LE and BEND cells lack or have very low levels of IRF2 mRNA (Song & Spencer, unpublished results); thus, they are fully responsive to IFNT in vitro (Johnson et al. 1999b, Perry et al. 1999, Stewart et al. 2001). In human 2fTGH cells, Type I IFNB (interferon beta) can induce IFIH1 expression, but this is not the case for STAT1 null U3A cells derived from 2fTGH cells (Kang et al. 2004). Thus, the classical JAK-STAT-IRF signaling pathway active in endometrial stroma and glands, and perhaps resident immune cells, is likely responsible for IFNT induction of IFIH1 via activation and formation of the ISGF3 complex (Kang et al. 2004). One interesting finding of the present studies was the loss of RSAD2 mRNA in the middle to deep endometrial glands between days 16 and 18 of pregnancy. This loss correlates with a reduction in IFNT production by the conceptus as well as a decline in IRF1 abundance in those glands (Choi et al. 2001b). Available evidence supports the concept that distinct cell-type specific differences exist in the ruminant endometrium with respect to responses to IFNT from the conceptus between the endometrial glands, stroma and resident immune cells.
The IFNT-stimulated genes in endometria of ruminants are hypothesized to be important for conceptus implantation (Hansen et al. 1999b, Spencer et al. 2004b, Klein et al. 2006). RSAD2 contains a radical S-adenosylmethionine (SAM) domain that catalyzes diverse reactions, including unusual methylations, isomerization, sulfur insertion, ring formation, anaerobic oxidation, and protein radical formation. Radical SAM proteins function in DNA precursor, vitamin, cofactor, antibiotic and herbicide biosynthesis, and biodegradation pathways (Sofia et al. 2001) which could be important in endometrial cells during the peri-implantation period to support conceptus development and implantation. IFIH1 (alias melanoma differentiation associated gene 5) is a RNA helicase induced during differentiation, cancer reversion, and programmed cell death (Kang et al. 2002, 2004). IFIH1 acts to sense intracellular viral infection and mediate a signal for innate antiviral responses including production of Type I IFNs (Kang et al. 2002, Yoneyama et al. 2005). Other Type I IFNs (IFNA and IFNB) are not induced in the endometrium in response to IFNT (Spencer & Bazer, unpublished results).
One biological role of RSAD2 and IFIH1 could be to prevent viral infection of the uterus during the critical peri-implantation period of pregnancy, particularly when the conceptus does not have a developed immune system or antiviral defenses. RSAD2 and IFIH1 are implicated in establishing an antiviral state by modulation of innate immune responses. For example, stable expression of RSAD2 in fibroblasts inhibits human cytomegalovirus infection (Chin & Cresswell 2001). Given that IFIH1 also has growth suppressive properties, IFNT induction may suppress the activation of cells within the endometrium, which could be beneficial for pregnancy. In other species such as rodents and humans, resident and recruited immune cells within the endometrium play important roles in placentation and the success of pregnancy (Croy et al. 2003a, 2003b). Unfortunately, knowledge of which immune cells are present in the ovine uterus during pregnancy and their biological functions is sparse. During the estrous cycle, the density of macrophages and T lymphocytes in the ovine and bovine uteri do not change (Hansen 1998). However, during early pregnancy, the number of CD45R+ lymphocytes increases in both endometrium (Segerson et al. 1991) and uterine and jugular venous blood (Lee et al. 1988, Alders & Shelton 1990). It has been postulated that these are NK (natural killer) cells that produce factors to enhance establishment of pregnancy. In the present study, the number of IFIH1-and, in particular, RSAD2-positive immune cells markedly increased in the endometria during pregnancy and in response to IFNT, but it is not clear whether these cells were recruited in response to IFNT or already present and stimulated by IFNT. The IFNT stimulated resident immune cells in the endometrium may migrate from the uterus, because IFNT-stimulated genes are higher in the peripheral blood leukocytes isolated from pregnant as compared with non-pregnant ewes and cows (Yankey et al. 2001). Eosinophils are also present in the endometrium of early pregnant ewes, and their numbers increase between days 11 and 19 of early pregnancy, perhaps due to actions of both P4 and perhaps IFNT (Asselin et al. 2001). In fact, IFNT possesses immunoregulatory activity and can inhibit mitogen-induced lymphocyte proliferation (Newton et al. 1989, Tekin et al. 2000) as well as modulate activity of NK cells (Tuo et al. 1993, Tekin & Hansen 2002). These effects of IFNT may prevent immune cell-mediated destruction of the conceptus (Hansen 1995). Finally, some IFNT-stimulated genes, such as CXCL10, from immune cells may have direct effects on conceptus implantation (Nagaoka et al. 2003, Imakawa et al. 2006). Collectively, available evidence supports the hypothesis that RSAD2 and IFIH1 modulate uterine receptivity to conceptus implantation by induction of an antiviral state and modulation of immune cell functions.
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Footnotes |
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionAcknowledgementsReferences |
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