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Center for Animal Biotechnology and Genomics and Department of Animal Science, Texas A&M University, College Station, Texas 77843
Address all correspondence and requests for reprints to: Fuller W. Bazer, Center for Animal Biotechnology and Genomics, 442 Kleberg Center, 2471 TAMU, Texas A&M University, College Station, Texas 77843-2471. E-mail: fbazer{at}cvm.tamu.edu.
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Abstract |
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. Other endometrial CTS genes were also regulated by progesterone alone (CTSB, CTSK, CTSS, and CTSZ) or progesterone and IFN (CTSH, CTSK, CTSS, and CTSZ). These results indicate that CTS of endometrial and conceptus origin may regulate endometrial remodeling and conceptus implantation, endometrial CTS genes are regulated by ovarian and placental hormones, and CTSL is a novel IFN-stimulated gene expressed only in luminal epithelium and superficial glandular epithelium of the endometrium. |
Introduction |
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Regulation of CTS expression in the ovine uterus and conceptus has not been reported. Trophoblast invasion in ruminants (sheep, cattle, goats) is limited to fusion of migrating binucleate cells with uterine epithelium, but considerable tissue remodeling and angiogenesis occur within the endometrium at implantation, which is associated with the cysteine and serine proteases and production of MMPs by the endometrium and conceptus (12, 14). Endometrial function during this period of pregnancy appears to be primarily regulated by progesterone from the corpus luteum and hormones from the conceptus, including interferon (IFN) (15, 16). IFN is the signal for maternal recognition of pregnancy in ruminants and is produced between d 10 and 21–25 of pregnancy in sheep by the mononuclear trophoblast cells of the conceptus (17, 18). In sheep, IFN acts in a paracrine manner on endometrial epithelia to inhibit transcription of the estrogen receptor-
and oxytocin receptor genes (17, 19), thereby preventing endometrial release of luteolytic pulses of prostaglandin F2 (20). The antiluteolytic actions of IFN are required for maintenance of a functional corpus luteum and secretion of progesterone, the essential hormone of pregnancy (20). IFN also induces or stimulates expression of a number of genes in the endometrium that are hypothesized to play important biological roles in conceptus implantation (21). This study determined effects of the estrous cycle, pregnancy, progesterone, and IFN on expression of selected CTS genes in the ovine endometrium. Results indicated that a number of CTS genes are expressed in the endometrium and conceptus during early pregnancy and regulated by progesterone and/or IFN. In particular, CTSL was found to be novel gene stimulated by progesterone and IFN only in endometrial luminal (LE) and superficial ductal glandular epithelia (sGE).
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Materials and Methods |
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Experimental design
Study 1. At estrus (d 0), ewes were mated to either an intact or vasectomized ram as described previously (22) and then hysterectomized (n = 5 ewes/d) on d 10, 12, 14, or 16 of the estrous cycle or d 10, 12, 14, 16, 18, or 20 of pregnancy. Pregnancy was confirmed on d 10–16 after mating by the presence of a morphologically normal conceptus(es) in the uterus. At hysterectomy, several sections (
0.5 cm) from the midportion 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). Several sections (1–1.5 cm) from the middle of each uterine horn were embedded in Tissue-Tek OCT compound (Miles, 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 subsequent RNA or protein extraction. In monovulatory pregnant (PX) 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 study. Uterine flushes were clarified by centrifugation (3000 x g for 30 min at 4 C) and frozen at –80 C for Western blot analysis.
Study 2. Cyclic (C) ewes (n = 20) were checked daily for estrus and then ovariectomized and fitted with indwelling uterine catheters on d 5 as described previously (23). Ewes were then assigned randomly (n = 5 per treatment) to receive daily im injections of progesterone and/or a progesterone receptor (PR) antagonist (ZK 136,317; Schering AG, Berlin, Germany) and intrauterine infusions of control serum proteins and/or recombinant ovine IFN protein as follows: 1) 50 mg progesterone (P, d 5–16) and 200 µg control (CX) serum proteins (d 11–16) (P+CX); 2) P and 75 mg ZK 136,317 (d 11–16) and CX proteins (P+ZK+CX); 3) P and IFN (2 x 107 antiviral units, d 11–16) (P+IFN); or 4) P and ZK and IFN (P+ZK+IFN). Steroids 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 IFN (5 x 106 antiviral units/horn per injection). Recombinant ovine IFN was produced in Pichia pastoris and purified as described previously (24). Proteins were prepared for intrauterine injection as described previously (23). This regimen of progesterone and recombinant ovine (ro)IFN mimics the effects of progesterone and the conceptus on endometrial expression of hormone receptors and IFN-stimulated genes during early pregnancy in ewes (25, 26, 27, 28). All ewes were hysterectomized on d 17, and the uteri and endometria processed as described in study 1.
RNA isolation
Total cellular RNA was isolated from frozen ipsilateral endometrium (studies 1 and 2) using Trizol reagent (Life Technologies, Inc.-BRL, Bethesda, MD) 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 CTSB, CTSK, CTSL, CTSH, CTSS, CTSD, and CTSZ
Partial cDNAs for ovine CTSB, CTSD, CTSK, CTSL, CTSH, CTSS, and CTSZ mRNAs were amplified by RT-PCR using total RNA from endometrial tissues from d 16–18 of pregnancy using specific primers (Table 1
). PCR amplification was conducted as follows for ovine CTSB, CTSK, CTSL, CTSH, CTSS, CTSD and CTSZ : 1) 95 C for 5 min; 2) 95 C for 45 sec; 59.1 C (for CTSB and CTSH), 56.5 C (for CTSD, CTSK, CTSL, and CTSZ), or 64.5 C (for CTSS) for 1 min; and 72 C for 1 min for 35 cycles; and 3) 72 C for 10 min. Partial cDNAs of the correct size were cloned into pCRII using a T/A cloning kit (Invitrogen) and their sequences verified by sequencing.
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-32P]uridine 5-triphosphate. Denatured total endometrial RNA (20 µg) from each ewe in studies 1 and 2 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). After washing, the blots were digested with ribonuclease A and radioactivity associated with slots quantified using a Typhoon 8600 MultiImager (Molecular Dynamics, Piscataway, NJ). Data are expressed as relative units.
In situ hybridization analyses
Location of mRNA expression in sections (5 µm) of the ovine uterus was determined by radioactive in situ hybridization analysis as described previously (28, 29). Radiolabeled antisense and sense cRNA probes were generated by in vitro transcription using linearized plasmid template, RNA polymerases, and [-35S]uridine 5-triphosphate. Deparaffinized, rehydrated, and deproteinated uterine tissue sections were hybridized with radiolabeled antisense or sense cRNA probes. After hybridization, washing, and ribonuclease A digestion, slides were dipped in NTB-2 liquid photographic emulsion (Kodak, Rochester, NY) and exposed at 4 C for 2 wk. Slides were developed in Kodak D-19 developer, counterstained with Gill’s hematoxylin (Fisher Scientific, Fairlawn, NJ), and then dehydrated through a graded series of alcohol to xylene. Coverslips were then affixed with Permount (Fisher Scientific). Images of representative fields were recorded under bright-field or dark-field illumination using an Eclipse 1000 photomicroscope (Nikon Instruments Inc., Lewisville, TX) fitted with a Nikon DXM1200 digital camera.
Immunohistochemistry
Immunocytochemical localization of immunoreactive CTSL protein in the ovine uterus was performed as described previously (22) in uterine tissue cross-sections from studies 1 and 2 using rabbit antihuman CTSL polyclonal antibody (catalog no. 3192-100; BioVision, Mountain View, CA) at a final concentration of 1 µg/ml. Antigen retrieval was performed by using boiling citrate buffer as described previously (30). Negative controls included substitution of the primary antibody with nonimmune rabbit IgG (Sigma Chemical Co., St. Louis, MO) at the same final concentration.
Western blot analyses
Protein concentrations of uterine flushes were determined using the Bradford protein assay (Bio-Rad Laboratories, Hercules, CA) with BSA as the standard. Proteins were denatured and separated by 12% SDS-PAGE and Western blot analysis conducted as described previously (22) by using enhanced chemiluminescence (SuperSignal West Pico, Pierce, Rockford, IL) and X-OMAT AR x-ray film (Kodak) according to the manufacturer’s recommendations. Immunoreactive CTSL protein was detected using rabbit antihuman CTSL polyclonal antibody (catalog no. 3192-100; BioVision) at 0.5 µg/ml.
Statistical analyses
Data from slot blot hybridization analyses were subjected to least squares ANOVA using the general linear models procedures of the Statistical Analysis System (Cary, NC). Slot blot hybridization data were corrected for differences in sample loading using the 18S rRNA data as a covariate. Data from study One were analyzed for effects of day, pregnancy status (C or PX), and their interaction. Effects of day were determined by least squares regression analysis. Data from study 2 were analyzed using preplanned orthogonal contrasts (P+CX vs. P+IFN, P+CX vs. P+ZK+CX, and P+IFN vs. P+ZK+IFN). Data are presented as least squares means with overall SE values.
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Results |
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). Expression of CTSB mRNA was lowest on d 10 and increased to d 16 or 20 in C and PX ewes, respectively (linear effect of day, P < 0.01). Endometrial levels of CTSD mRNA did not change in C ewes but increased from d 10–20 in PX ewes (linear effect of day, P < 0.01). CTSH mRNA levels increased from d 10–14 in C ewes and from d 10–20 in PX ewes (linear effect of day, P < 0.01). In contrast, CTSK mRNA did not change (P > 0.10) in endometria of C and PX ewes. CTSL mRNA was affected (P < 0.05) by day, status, and their interaction. In C ewes, CTSL mRNA increased from d 10–14 and then declined to d 16 (quadratic effect of day, P < 0.05). In PX ewes, CTSL mRNA increased about 8-fold between d 10 and 18 (linear effect of day, P < 0.01). Furthermore, CTSL mRNA levels in the endometrium were greater on d 14 and 16 in PX than C ewes (day x status, P < 0.05). Endometrial CTSS and CTSZ mRNA levels were not affected by pregnancy status or day or their interaction (P > 0.10).
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). Abundant CTSB mRNA was detected in the trophectoderm of the conceptus. CTSD mRNA was expressed at low levels in the endometrial LE and sGE; however, abundant CTSD mRNA was detected in the trophectoderm of the conceptus. CTSH mRNA was expressed at moderate levels in the endometrial LE and GE, particularly on d 18 and 20 in PX ewes. In C and PX ewes, CTSK mRNA was expressed at moderate levels in the endometrial LE and stroma as well as cells within the stroma that appeared to be immune cells based on their morphology and location.
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). Furthermore, CTSL mRNA was expressed by conceptus trophectoderm on d 18 and 20 of PX. CTSS mRNA was detected at low levels in the endometrial LE and cells within the stroma that appeared to be immune cells based on their morphology and distribution. The number of CTSS mRNA-positive immune-like cells increased between d 14 and 16 of pregnancy. CTSZ mRNA was detected at low levels specifically in the endometrial LE and sGE as well as conceptus trophectoderm on d 18 and 20 of pregnancy. No differences in expression of CTS mRNAs in the LE or stroma of the intercaruncular endometria were found when compared with the caruncular endometria in the uterus of either C or PX ewes (data not shown).
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CTSL protein in the endometrium and uterine lumen (study 1)
Consistent with in situ hybridization analyses, immunoreactive CTSL protein was observed predominantly in the LE and sGE in the endometrium of C and PX ewes (Fig. 4A). In PX ewes, the amount of immunoreactive CTSL protein increased from d 10–16 and was observed predominantly near the apical surface of the LE. Less immunoreactive CTSL protein was detected in the stroma and conceptus trophectoderm.
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). Furthermore, the cleaved and active forms of CTSL, made up of 21- and 5-kDa subunits, were also detected at very low abundance in uterine flushings from PX ewes.
Effects of progesterone and IFN on endometrial CTS expression (study 2)
To determine whether P and IFN regulated CTS gene expression in the endometrium, a study was conducted as described in Materials and Methods (Fig. 5A). As illustrated in Fig. 5B, treatment with P increased CTSL mRNA in the endometrium (P+CX vs. P+ZK+CX, P < 0.001), which was further stimulated by about 3-fold in ewes receiving intrauterine administration of roIFN (P+CX vs. P+IFN, P < 0.01), but roIFN did not stimulate CTSL mRNA in ewes receiving the ZK antiprogestin (P+IFN vs. P+ZK+IFN, P > 0.10). In situ hybridization analyses revealed that CTSL mRNA was expressed abundantly only in the endometrial LE and sGE of ewes treated with P (P+CX and P+IFN) (Fig. 5C).
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in ewes receiving P (P+CX vs. P+IFN, P < 0.01), whereas roIFN increased CTSB mRNA in ewes receiving P and ZK (P+ZK+CX vs. P+ZK+IFN, P < 0.04) (Fig. 6). Expression of CTSD mRNA was not affected (P > 0.10) by steroid or intrauterine roIFN treatment. Endometrial CTSH mRNA was increased by IFN (P+CX vs. P+IFN, P < 0.001) but not affected by other treatments (P > 0.10). CTSK mRNA was decreased by P (P+CX vs. P+ZK+CX, P < 0.02) but increased by roIFN in ewes receiving P (P+CX vs. P+IFN, P < 0.01) or P+ZK (P+ZK+CX vs. P+ZK+IFN, P < 0.001). CTSS mRNA was also stimulated by P (P+CX vs. P+ZK+CX, P < 0.02). In ewes receiving P only, roIFN decreased CTSS mRNA in the endometrium (P+CX vs. P+IFN, P = 0.06). CTSZ mRNA was slightly stimulated by P (P+CX vs. P+ZK+CX, P < 0.05) and increased by roIFN in ewes receiving P alone (P+CX vs. P+IFN, P < 0.01) or P+ZK (P+ZK+CX vs. P+ZK+IFN, P < 0.01).
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Discussion |
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Interestingly, the ovine placenta expresses large numbers of aspartic proteinase inhibitor genes, termed pregnancy-associated glycoproteins (31), and the endometrial glands express large amounts of serine protease inhibitors, termed serpins or uterine milk proteins (32), that could regulate the activity of endometrial CTS identified in the present study. Therefore, the molecular control of expression of CTS in the ovine endometrium may play an important role in establishing a regulatory network of multiple proteolytic enzymes responsible for ECM remodeling during implantation and placentation. Although decidualization of the endometrial stroma does not occur in sheep, the endometrium undergoes dramatic remodeling after pregnancy recognition and establishment between d 12 and 20 of early pregnancy. In the intercaruncular endometrium, the endometrial epithelium is removed by the trophoblast giant binucleate cells during synepitheliochorial placentation, the stroma becomes very compact and begins to express new genes such as osteopontin, and the glands undergo hypertrophy followed by hyperplasia (33, 34, 35, 36). In the caruncular endometrium, the placental cotyledons attach to the maternal caruncles and develop into placentomes (35). These morphogenetic and differentiation events undoubtedly involve regulation by CTS and extensive remodeling of the ECM.
The present studies found that CTSL mRNA was particularly abundant in the endometrial LE and sGE and up-regulated during early pregnancy in association with conceptus elongation and implantation (16). CTSL is normally localized in lysosomes, in which it plays a major role in intracellular protein catabolism. In the present studies, the 38- to 40-kDa latent pro-CTSL form of CTSL protein was abundant in uterine flushings from d 12, 14, and 16 PX ewes. This latent pro-CTSL must be cleaved by proteases, such as MMPs, to generate the active two-chain form made up of 21- and 5-kDa subunits (1). The presence of the pro-CTSL in uterine flushings from PX ewes between d 12 and 16 of pregnancy suggests that CTSL is secreted by the endometrial LE and/or conceptus. Indeed, the synthesis and secretion of the 39-kDa pro-CTSL has been demonstrated for many tumors, including cancers of the kidney, lung, colon, breast, and ovary (37). In rodents, interactions of CTSB, CTSL, and cystatin C, a CTSL inhibitor, are important for implantation and placentation because inhibition of endometrial CTSL and CTSB results in abnormal embryonic development and uterine decidualization during the periimplantation period (4). Invasion by the ectoplacental cone of mouse trophoblast was prevented by cysteine proteinase inhibitors in vitro (38). Recently Cheon et al. (39) found that cytotoxic T lymphocyte antigen-2ß, a cysteine protease inhibitor, was up-regulated by progesterone in the decidua and proposed to regulate blastocyst implantation by neutralizing the activities of one or more proteases, including CTSL, generated by the proliferating trophoblast. CTSL has been studied in uteri of cats (6, 7, 8), pigs (9), and mice (4, 40). In cats, CTSL is localized to the GE and can be detected in the uterine lumen, in which it is implicated in blastocyst invasion (6). In pigs, CTSL was also found to be expressed in the endometrial GE and as a progesterone-regulated component of the uterine lumen during implantation and placentation (9). Thus, available results suggest that CTSL may be an essential regulator of endometrial remodeling and conceptus implantation during pregnancy in sheep as well as many other mammals. CTSL is capable of degrading ECM proteins, suggesting a role in conceptus attachment by altering the composition of the ECM present on the apical surfaces of the endometrial LE and/or trophoblast.
In the present study, temporal changes in expression of endometrial CTSL mRNA in C and PX ewes supported the hypothesis that ovarian progesterone regulates transcription of the CTSL gene in the endometrial LE. Similarly, an increase in CTSB, CTSD, CTSH, and CTSZ was also observed in the endometrium during early pregnancy. The increase in CTSL and CTSZ mRNAs in LE and sGE, between d 10 and 12 after estrus/mating, and CTSH mRNA in LE and GE, between d 14 and 16 after mating, is coincident with the disappearance of PR mRNA and protein in these epithelia (41). Similarly, the decrease in CTSL and CTSZ mRNAs between d 14 and 16 of the cycle is coincident with the reappearance of PR protein in endometrial LE. In study 2, CTSL mRNA was detected in endometrial LE and sGE of ovariectomized ewes treated with P for 12 d, but this expression was prevented by administration of the PR antagonist ZK 136,317. Continuous exposure of the sheep uterus to P for 8–10 d down-regulates PR expression in endometrial LE and sGE but not stroma or myometrium (25). PRs are present in the endometrial epithelia of P+ZK-treated sheep (42) because PR antagonists prevent the inhibitory effects of P on the PR gene expression. Consequently, P modulation of CTSL mRNA may be attributed, at least in part, to down-regulation of PR by P that occurs in LE and sGE between d 10 and 12 of the cycle and pregnancy (15, 41). Thus, PR loss in endometrial epithelia may reprogram these cells, allowing them to increase expression of genes associated with implantation (15, 16). Alternatively, P may act on PR-positive stromal cells to induce them to express growth factors or changes in the ECM that regulate expression of selected epithelial genes (15).
In addition to regulation by P, the present studies indicate that CTSH, CTSK, CTSL, and CTSZ are regulated by IFN. IFN is the pregnancy recognition hormone in sheep that acts on the endometrium to prevent development of the luteolytic mechanism, thereby maintaining the corpus luteum and production of P (16). Of particular note, CTSL is a novel gene stimulated by IFN in endometrial LE and sGE as expression between d 10 and 18 of early pregnancy and parallels the increase in production of IFN by the elongating conceptus, which is maximal on d 16 (43). In study 2, intrauterine administration of roIFN increased CTSL mRNA but only in P-treated ewes. One hypothesis is that IFN can stimulate transcription of the CTSL gene only in the absence of repression by liganded PR. Alternatively, the PR-positive stroma may produce a progestamedin that is also required for LE and sGE to respond to IFN (16). The signaling pathway whereby IFN regulates transcription of the CTSL gene is not known, but it clearly does not involve the classical Janus kinase-signal transducer and activator of transcription signaling pathway (15, 19, 26, 29). To date, WNT7A and LGALS15 (galectin-15) are the only other genes identified in endometrial LE and sGE that are induced or stimulated by IFN, respectively (26, 44). Thus, the diverse actions of IFN on the endometrium include repression of genes, including ER, to abrogate activation of the luteolytic mechanism as well as stimulation of genes that are critical to implantation, placentation, and conceptus growth and development (15). Knowledge of mechanisms whereby IFN stimulates CTSL gene expression in the endometrial LE and sGE is expected to unravel a nonclassical signaling pathway for type I IFNs. Future studies will focus on the role of CTSL, other CTS family members, and their inhibitors in endometrial remodeling and conceptus implantation and placentation.
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Footnotes |
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Abbreviations: C, Cyclic; CTS, cathepsin; CX, control; ECM, extracellular matrix; IFN, interferon; LE, luminal epithelium; MMP, matrix metalloproteinase; P, progesterone; PR, progesterone receptor; PX, pregnant; ro, recombinant ovine; sGE, superficial glandular epithelium.
Received June 24, 2005.
Accepted for publication August 2, 2005.
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References |
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-Interferon: pregnancy recognition signal in ruminants. Proc Soc Exp Biol Med 213:215–229[CrossRef][Medline]
promoter and functional regulation by ovine interferon-. Endocrinology 142:2879–2887 in the uterus during early pregnancy. J Reprod Fertil Suppl 54:329–339[Medline]
, placental lactogen, and growth hormone on the ovine uterus. Biol Reprod 61:1409–1418 by Pichia pastoris. J Interferon Cytokine Res 16:119–126[Medline]
regulates expression of endometrial receptors for estrogen and oxytocin but not progesterone. Biol Reprod 53:732–745[Abstract]
independent of signal transducer and activator of transcription 1. Endocrinology 144:5203–5214 on 2',5'-oligoadenylate synthetase expression in the ovine uterus. Biol Reprod 64:1392–1399 on the endometrium of cyclic ewes. Biol Reprod 61:464–470This article has been cited by other articles:
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