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Pregnancy |
Department of Obstetrics and Gynecology, Evanston Northwestern Healthcare, Feinberg School of Medicine, Northwestern University, Evanston, Illinois 60201
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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gene regulation, parturition, pregnancy uterus
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Prostaglandins stimulate uterine contractions and cervical ripening during labor. Both prostaglandin E2 (PGE2) and prostaglandin F2
(PGF2) are produced by maternal and fetal tissues during parturition, and the concentration of both increases in the amniotic fluid during labor [9]. Administration of prostaglandin synthase inhibitors suppresses uterine activity and prolongs the length of pregnancy [10]. Primary prostaglandins are formed from arachidonic acid through activity of the cyclooxygenase (COX) enzyme complex. The COX catalyzes the first committed step of prostaglandin synthesis, the initial conversion of arachidonic acid to PGH2. Two isoforms of COX have been identified, COX-1 and COX-2, which are also known as prostaglandin endoperoxide H synthase (PGHS)-1 and PGHS-2, respectively. The COX-1 is constitutively expressed in many tissues with little regulation in synthesis, whereas COX-2 is inducible in response to a variety of growth factors and inflammatory stimuli. Mice lacking the gene for PGF2 receptor [11] or COX-1 [12] have delayed onset of labor because of the roles of these factors in regulating luteolysis and myometrial expression of oxytocin receptors. Recent studies demonstrate a dramatic increase of COX-1, but not of COX-2, transcripts and activity in the uterus [13] and fetal membranes [14] in mice during late gestation. In one report, both COX-1 and COX-2 expression within the uterus were significantly altered within 2 h of lipopolysaccharide (LPS) administration, with COX-2 increasing and COX-1 decreasing [15].
The NAD+-dependent 15-hydroxyprostaglandin dehydrogenase (PGDH) is responsible for the initial inactivation of prostaglandins, catalyzing the conversion of primary prostaglandins to their biologically inactive 15-keto derivatives. Expression and activity of PGDH have been demonstrated in fetomaternal tissues of different species. Reduced PGDH expression and activity in myometrium and chorion have been suggested in association with term and preterm birth in humans [9]. However, in the mouse, PGDH mRNA increased in placentas and fetal membranes [16] and decreased in uterus [13] during late gestation. These studies suggest that COX and PGDH in the fetomaternal environment may play important roles in the initiation of labor, but the relative contributions of the maternal and the fetal tissues to COX and PGDH activity during infection are still incompletely defined.
We have reported a model of infection-induced preterm birth in mice following intrauterine inoculation with live or heat-killed Escherichia coli (HKE). Intrauterine inoculation of pregnant CD-1 mice with HKE on Day 14.5 of a 19- to 20-day gestation leads to dose-dependent preterm delivery. This process mimics human infection-associated preterm labor in many important ways, such as the expression of proinflammatory cytokines [17–19]. We have demonstrated significant increases in interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF) within uteri and fetal membranes following HKE treatment in this mouse model [19], as has been demonstrated in humans. However, several groups have shown that blockade of IL-1 and/or TNF by using IL-1-receptor antagonist, soluble TNF-receptor Fc fusion protein, or IL-1 and IL-1-receptor knockout mice does not prevent preterm delivery in mice after administration of bacteria or LPS [20–22]. Thus, it remains uncertain whether inflammatory cytokines are critical mediators of the signals by which bacterial exposure causes labor.
A gram-negative bacterial cell wall component, LPS can induce expression of inflammatory cytokines and prostaglandins and leads to preterm birth in pregnant mice [6, 8] and rats [23] following intraperitoneal injection or intrauterine infusion. The current consensus is that LPS signaling occurs through a heterotrimeric receptor complex, of which the toll-like receptor 4 (TLR-4) protein is a critical component. A point mutation in the intracytoplasmic region of TLR-4 is responsible for the 20- to 40-fold LPS hyporesponsiveness of C3H/HeJ mice [24]. The defective Lps allele affects the functions of several cell types, including the macrophage, which on activation normally secretes a large array of proinflammatory factors and is critical for the innate immune response to bacterial pathogens.
In the present study, we used inbred pregnant C3HeB/FeJ mice (TLR-4-normal) and C3H/HeJ (TLR-4-mutant) mice to test the hypothesis that E. coli induces preterm labor via TLR-4 and to characterize the role of TLR-4 in the fetal and maternal expression of prostaglandin metabolic enzymes during the early phase of bacterially induced preterm labor.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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All animals were treated in accordance with the Guide for Care and Use of Laboratory Animals and with the approval of the Animal Care and Use Committee of Evanston Northwestern Healthcare and Northwestern University. Inbred C3HeB/FeJ mice and C3H/HeJ mice (Jackson Laboratory, Bar Harbor, ME) were housed at an ambient temperature of 72°F and a 12L:12D photoperiod. Animals had free access to food and water. Females (age, 8–14 wk) were mated with fertile males. Mating was verified by the presence of a vaginal plug. On Day 14.5 after plugging (
75% of the typical 19- to 20-day gestation), surgery was performed (see below).
Preparation of HKE
Escherichia coli bacteria (American Type Culture Collection no. 12014) were grown to log phase at 37°C in Luria-Bertani broth (Invitrogen, Carlsbad, CA) and concentrated by centrifugation. They were then washed three times with phosphate-buffered saline (PBS) and suspended in PBS. Serial dilutions of the E. coli suspension were plated in triplicate to determine the concentration of bacteria by overnight culture. Immediately after plating these dilutions, the E. coli within the PBS suspension were killed by boiling in water for 5 min, and the suspension was then frozen at -20°C. Bacterial killing was verified by lack of growth overnight in broth and solid media. After the concentration of the bacterial suspension was determined, the HKE stock was thawed and diluted to a concentration of 1 x 1010 organisms/ml. This latter suspension was vortexed, aliquoted, and frozen at -80°C. Before each experiment, one of the frozen killed bacterial aliquots was thawed, vortexed, and diluted as necessary to the desired concentration.
Inoculation procedure and specimens
Pregnant mice were anesthetized with 16–18 µg/g body weight of a mixture of 2.5% (w/v) tribromoethyl alcohol and 2.5% (v/v) tert-amyl alcohol (Aldrich Chemical, Milwaukee, WI) in PBS. A 1.5-cm midline incision was made in the lower abdomen, and 100 L of pyrogen-free PBS or HKE suspended in PBS were injected into the midsection of the right uterine horn at a site between two adjacent fetuses. The abdominal incision was then closed in two layers using interrupted 5-0 coated vicryl sutures through the peritoneum and staples at the skin.
To establish the dose-response relationship between bacterial exposure and preterm delivery, a group of 40 pregnant C3HeB/FeJ (TLR-4-normal) mice and 20 pregnant C3H/HeJ (TLR-4-mutant) mice were monitored after inoculation of variable amounts of HKE. These animals underwent twice-daily observations in which health status was recorded. Mice that delivered prematurely (defined as the finding of at least one pup in the cage or the lower vagina within 48 h of surgery) or delivered at term underwent autopsy when fetuses were found in the cage. Some mice not delivered prematurely underwent autopsy 72 h after surgery to determine fetal status.
For measurement of COX and PGDH transcripts within fetomaternal tissues, a second group of pregnant C3HeB/FeJ and C3H/HeJ mice were inoculated with either pyrogen-free PBS or HKE sufficient to cause preterm delivery in 100% of C3HeB/FeJ mice (5 x 109 organisms). Animals were killed with carbon dioxide gas, and tissues were collected at 0, 1, 2, and 4 h after surgery for C3HeB/FeJ mice or at 4 h after surgery for C3H/HeJ mice (5 animals per group per time point). Harvest times early during the course of infection were selected, because previous data showed that levels of cytokines, enzymes, and transcription factors change in myometrium in CD-1 mice within 4 h of inoculation with high-dose HKE [18]. The abdomen was opened, and the injected uterine horn was cut away from its mesometrium and then incised longitudinally along the antimesenteric border. The gestational sacs and placentas were shelled out, and the right uterine horns were then washed in ice-cold PBS. The decidual cap at each implantation site was removed by sharp dissection, leaving behind the myometrium. The individual sacs surrounding each fetus were cut away, and fetus, fetal membranes, and placentas were washed in cold PBS. These specimens were then minced and immediately frozen in liquid nitrogen. Decidual caps, fetal membranes, placentas, and fetuses were pooled by tissue for each pregnancy.
RNA extraction
Total RNA was extracted from tissue specimens after homogenization in TRIzol reagent (Invitrogen, Carlsbad, CA) according to the manufacturer's instructions. The quantity and quality of the RNA was verified by spectrophotometry and formaldehyde gel electrophoresis, respectively.
Reverse Transcription-Polymerase Chain Reaction
Five to eight micrograms of total RNA were used as a template for cDNA synthesis. The cDNA was prepared using random primers and the Moloney murine leukemia virus reverse transcriptase system (Invitrogen). Polymerase chain reaction (PCR) primers were designed and synthesized on the basis of reported mouse cDNA sequences for COX-1, COX-2, PGDH, and ß-actin. Sequences of the primers and amplicon lengths were as follows: for COX-1, 5'-gcatgtggctgtggatgtca-3' (forward) and 5'-ggtcttggtgttgaggcaga-3' (reverse), with an amplicon of 388 base pairs (bp) corresponding to nucleotides 1395–1782 in the mouse COX-1 cDNA (GenBank accession no. BC005573.1); for COX-2, 5'-acactctatcactggcaccc-3' (forward) and 5'-gaagggacaccccttcacat-3' (reverse), with an amplicon of 585 bp corresponding to nucleotides 1229–1813 in the mouse COX-2 cDNA (GenBank accession no. NM011198.1); for PGDH, 5'-atttcggaagattggatattttggtc-3' (forward) and 5'-ttcaatgagatctattaatccattgg-3' (reverse), with an amplicon of 461 bp corresponding to nucleotides 269–729 in the mouse PGDH cDNA (GenBank accession no. NM008278.1); and for ß-actin, 5'-attgtgatggactccggtgacgg-3' (forward) and 5'-atcttgatcttcatggtgctagg-3' (reverse), with an amplicon of 536 bp corresponding to nucleotides 373–908 in the mouse ß-actin cDNA (GenBank accession no. M12481.1). Each PCR reaction was performed in a 30-µl mixture containing 1.0 µl of cDNA, 10 pmol of each primer, 0.25 mM dNTP, and 1.25 U of Taq DNA polymerase (Roche Applied Science, Indianapolis, IN). Cycling conditions were as follows: denaturation for 40 sec at 94°C, annealing for 30 sec at 62°C, and extension for 60 sec at 72°C. After sequencing of COX-1, COX-2, PGDH, and ß-actin PCR products to confirm the gene specificity of these fragments, the optimal number of amplification cycles was determined in pilot reactions and were as follows: 22 cycles for ß-actin, 28 cycles for COX-1, 30 cycles for COX-2, and 38 cycles for PGDH.
After amplification, the PCR products were resolved by 1.2% agarose gel electrophoresis and visualized by staining with SYBR green-1 (Molecular Probes, Eugene, OR). Cycle numbers were determined empirically to yield amplicon bands of moderate intensity that represented a linear relationship between the number of cycles and the logarithm of the number of target molecules. The density of each DNA band was evaluated with a STORM-860 PhosphorImager and analyzed using the ImageQuantTM software package (both from Molecular Dynamics, Sunnyvale, CA) as reported previously [25]. The ratios of the signals for COX-1, COX-2, and PGDH to that of ß-actin were used as to determine the relative level of transcription expression. We have shown that ß-actin levels remain relatively stable within gestational tissues following HKE exposure in our mouse model over at least 4 h (unpublished data).
Statistical Analysis
All values in the figures and text are expressed as the mean ± SEM. Data sets were examined by one-way analysis of variance, and individual group means were compared with the Student unpaired t-test. For preterm delivery or fetal death, chi-square analyses was used with the Fisher exact correction when necessary. Differences between groups were considered to be significant when P < 0.05.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Six of six LPS-sensitive C3HeB/FeJ mice treated with vehicle delivered normal litters at term. Intrauterine injection of HKE demonstrated a dose-response relationship between inoculum size and incidence of preterm delivery (Table 1). Administration of the higher inocula (5 x 109 or 1 x 1010 bacteria) resulted in 100% preterm delivery within an average of 17.5 h after surgery. All offspring delivered preterm were dead. Among animals treated with the lower HKE inocula, intrauterine demise was observed in 20% of fetuses exposed to 1 x 107 bacteria (48 live fetuses and 12 dead fetuses in a total of six mothers killed on Day 3 after surgery) and in 55% exposed to 1 x 108 bacteria (17 live fetuses and 21 dead fetuses in a total of four mothers killed on Day 3 after surgery). In general, animals that were administered a delivery inoculum at or below 5 x 109 organisms appeared to be healthy or mildly ill (exhibiting mild piloerection, decreased mobility, and anorexia). Recovery after delivery appeared to be complete in most cases. The HKE inoculation at a dose of 1 x 1010 organisms caused maternal death or severe illness requiring five of six mice to be killed.
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Effect of TLR-4 on Bacterially Induced Preterm Delivery
To test the hypothesis that HKE induces preterm delivery via TLR-4, C3H/HeJ (TLR-4-mutant) mice were inoculated with quantities of HKE sufficient to cause preterm delivery in 100% of control C3HeB/FeJ mice. As shown in Table 1, preterm delivery occurred in none of eight TLR-4-mutant mice after treatment with 5 x 109 HKE and in two of seven after treatment with 1 x 1010 HKE. Among TLR-4-mutant mice treated with HKE, intrauterine demise was observed in 7% of fetuses exposed to 5 x 109 bacteria (26 live fetuses and two dead fetuses in a total of five mothers killed on Day 3 after surgery) and in 34% exposed to 1 x 1010 bacteria (23 live fetuses and 12 dead fetuses in a total of five mothers killed on Day 3 after surgery). Maternal illness was not seen with 5 x 109 bacteria and was only mild with 1 x 1010 bacteria.
Effects of HKE on COX-1, COX-2, and PGDH Transcripts in Maternal and Fetal Tissues
To determine whether transcription of the rate-limiting enzymes of prostaglandin synthesis (COX-1, COX-2, and PGDH) is regulated via TLR-4 during the early phase of bacterially induced preterm labor, semiquantitative reverse transcription-PCR was performed in pregnancy tissues obtained within 4 h after administration of either PBS or 5 x 109 HKE. In both mouse strains, bacterial exposure caused significant increases in COX-2 mRNA in myometrium and decidual caps but not in placentas and fetuses (Figs. 1–3). After HKE treatment, COX-2 mRNA becomes higher in maternal tissues (myometrium and decidual caps) than in fetal tissues in C3HeB/FeJ (normal) mice but not in C3H/HeJ (LPS-resistant) mice (Fig. 3). Basal levels of COX-1 mRNA in maternal tissues are higher than in fetal tissues in C3H/HeJ mice but not in C3HeB/FeJ mice. Levels of COX-1 remained unchanged in all tested maternal and fetal tissues in both strains (Figs. 1, 2, and 4).
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In normal (C3HeB/FeJ) mice, basal levels of PGDH were detectable but were lower in maternal tissues (myometrium and decidual caps) than in fetal tissues (Fig. 5). Levels of PGDH decreased significantly after HKE treatment in fetuses, fetal membranes, and myometrium, respectively, compared to those after control injections. In decidual caps, however, PGDH mRNA increased over its low basal level. In TLR-4-mutant (C3H/HeJ) mice, basal levels of PGDH were detectable in fetal tissues but not in maternal tissues (Fig. 5). Levels of PGDH remained unchanged in fetal tissues after HKE treatment.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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What is the mechanism by which bacteria cause labor? Previous studies have suggested a central role for prostaglandins and their synthetic and catabolic enzymes in this process. Variable reports have appeared concerning changes in COX expression at parturition in different species and in different circumstances. In the mouse, increased COX-1, but not COX-2, mRNA was reported during late gestation in the uterus [13] and fetal membranes [14], with increased COX-2 expression during term labor as well as ethanol- and LPS-induced preterm labor [26, 27]. In the rat, one study found that both COX-1 and COX-2 increased in myometrium with the onset of labor [28], but a different study reported increased expression of COX-2 only [29]. In sheep, increased COX-2 expression in endometrium, placenta, and myometrium was tightly associated with the onset of betamethasone-induced premature labor as well as spontaneous term labor [30]. In the baboon, COX-2 expression was increased in the lower uterine segment, cervix, and decidua but not in the uterine fundus, chorion, and placenta during late pregnancy and labor [31]. In humans, a large increase in COX-2 mRNA was found throughout late gestation in fetal tissues [32]. Both COX-1 and COX-2 have been reported to decrease or remain unchanged in the myometrium at the onset of labor [33] and to increase in the amnion during term labor [34].
The present results show that the levels of COX-2 transcripts in myometrium and decidua increase sharply in response to HKE treatment in both C3HeB/FeJ and C3H/HeJ mice, whereas COX-1 mRNA levels remain unchanged in the tissues tested for both mouse strains. These data suggest that TLR-4 signaling may not be essential for bacterially induced COX-2 gene expression, and they support the notion that COX-2, not COX-1, is the enzyme primarily responsible for increased prostaglandin biosynthesis during bacterially induced preterm labor. Several studies have shown that COX-2 antagonism may inhibit preterm labor in different species, such as human [35], sheep [36], rat [37], and mice [15, 38]. This conclusion is also supported by other data, such as a report that pretreatment of pregnant mice with COX-2 inhibitor, but not COX-1 inhibitor, prevented LPS-induced preterm labor [15].
To our knowledge, this is the first study to report that the basal levels of PGDH mRNA in mid- to late-pregnancy mice are higher in fetal tissues (fetus, fetal membranes, and placenta) than in maternal uterine tissues in both C3HeB/FeJ and C3H/HeJ mice. This tissue distribution of PGDH may allow for finely controlled regulation of prostaglandin activity in individual tissues during pregnancy. After HKE treatment, PGDH mRNA decreases significantly in the fetus, fetal membranes, and myometrium in TLR-4-normal mice but not in TLR-4 mutant mice. These data suggest that TLR-4 signaling may be involved in HKE-induced PGDH down-regulation. The role of prostaglandins generated in the fetus itself during gestation is still not clear. When the fetus is infected, fetal cortisol, cytokine, and prostaglandin production are increased [39, 40]. The currently accepted hypothesis is that PGDH represents a metabolic barrier in fetal tissues, either to prevent the passage of prostaglandins generated in these tissues to the uterus or to prevent prostaglandins generated in other tissues from damaging the fetus. During HKE-induced preterm labor, this functional barrier may break down, perhaps accounting for the fetal inflammatory response that has been observed during infection [40, 41].
In summary, the present study suggests that TLR-4 signaling is a critical factor in bacterially induced preterm labor. During bacterially induced preterm labor, TLR-4 signaling mediates PGDH gene down-regulation but is not essential for COX-2 gene up-regulation. Bacterially induced prostaglandin activity may be mediated primarily by increased synthesis in maternal tissues and decreased degradation in fetal tissues.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 Correspondence: Emmet Hirsch, Department of Obstetrics and Gynecology, Evanston Northwestern Healthcare, 2650 Ridge Avenue, Evanston, IL 60201. FAX: 847 733 5083; e-hirsch{at}northwestern.edu
Received: 28 May 2003.
First decision: 14 June 2003.
Accepted: 6 August 2003.
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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and interleukin-1 in a rabbit model of bacterially induced preterm pregnancy loss. Am J Obstet Gynecol 1992 167:1583-1588[Medline] metabolite levels. Am J Obstet Gynecol 2000 182:1496-501[CrossRef][Medline] synthase, mRNA in intrauterine tissues during betamethasone-induced premature labor and spontaneous term labor in sheep. J Soc Gynecol Investig 2001 8:69-76[CrossRef][Medline]This article has been cited by other articles:
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