Biol Reprod
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

BOR - Papers in Press, published online ahead of print May 28, 2003.
Biol Reprod 2003, 10.1095/biolreprod.103.015586
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
69/4/1165    most recent
biolreprod.103.015586v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Mackler, A. M.
Right arrow Articles by Yellon, S. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Mackler, A. M.
Right arrow Articles by Yellon, S. M.
Agricola
Right arrow Articles by Mackler, A. M.
Right arrow Articles by Yellon, S. M.
BIOLOGY OF REPRODUCTION 69, 1165–1169 (2003)
DOI: 10.1095/biolreprod.103.015586
© 2003 by the Society for the Study of Reproduction, Inc.

Pregnancy

Effects of Endotoxin and Macrophage-Related Cytokines on the Contractile Activity of the Gravid Murine Uterus1

Ari M. Mackler3, Travis C. Ducsay, Charles A. Ducsay, and Steven M. Yellon2

Center for Perinatal Biology, Department of Physiology, Loma Linda University School of Medicine, Loma Linda, California 92350


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Immune cell trafficking and activity are implicated in the parturition process, but little is known about the role of macrophages in control of uterine contractility at term. In the present study, we tested the hypothesis that endotoxin (lipopolysaccharide [LPS]) enhances uterine contractile activity through a mechanism that involves activation of resident macrophages. Various uterotonins and anti-inflammatory mediators were added to a standard muscle bath preparation that contained strips of uterus from Day 15 pregnant C3H/HeN mice. Spontaneous and agonist-induced contractile activity was enhanced following LPS treatment. LPS increased amplitude but not frequency of contractions. Addition of anti-inflammatory cytokines, interleukin 10 or transforming growth factor ß, to suppress macrophage activation did not block LPS-induced increases in contractility. By contrast, indomethacin given to block prostaglandin production suppressed the LPS-induced increase in amplitude of contractions. These findings suggest that an inflammatory response, possibly mediated by activation of macrophages and prostaglandins, participates in the regulation of amplitude but not frequency of contractile activity by the murine uterus before onset of parturition.

cervix, cytokines, oxytocin, parturition, uterus


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Enhanced immune cell activity is implicated in the etiology of a majority of cases of premature labor in humans [1, 2]. In pregnant mice, induction of an inflammatory immune response initiates labor [3–8]. Premature delivery can be induced within 24 h, 3–4 days before term, by systemic administration of the endotoxin lipopolysaccharide (LPS). Although LPS can induce both systemic and central reactions [9–12], the early termination of pregnancy may result from enhanced local production of uterotonins and inflammatory cytokines from the predominant immune cell, the macrophage, which resides in endometrial stroma and around myometrial bundles in the uterus [13–15]. Indeed, timing of various LPS treatments that cause preterm delivery occur when numbers of resident macrophages and activated macrophages are increased several fold compared with that in the nongravid or peripartum uterus [13, 14, 16].

Macrophages are a major component of inflammatory immune responses to LPS [17]. Activation of immune cells, a most likely consequence of LPS binding to toll-like receptor 4 (TLR-4), produces an inflammatory reaction [18–20]. As part of this cascade, increased production by activated macrophages of interleukin (IL) 1 and prostaglandins occurs; these factors are known to enhance uterine contractile activity [21, 22]. IL-1 mimics the effect of LPS in inducing preterm labor [7], but initiation of labor by IL-1 may be counteracted by transforming growth factor ß (TGFß) [23]. TGFß is an anti-inflammatory cytokine that along with IL-10 (a negative feedback product of macrophages) inhibits the activation of macrophages [24]. These cytokines may facilitate quiescence of the pregnant uterus before term and counter the influence of uterotonins to promote contractility. As part of the final common mechanism for initiation of labor, prostaglandins are essential for the process of parturition [25, 26], and LPS-induced preterm labor in mice is dependent upon prostaglandin production [27]. This evidence suggests that a local inflammatory cytokine response and actions by prostaglandins may contribute to LPS-mediated preterm birth.

Whether LPS or macrophage products directly regulate contractile activity by the pregnant uterus has yet to be determined. In mice, administration of LPS or inflammatory cytokines did not acutely alter spontaneous contractile activity [28]. However, in vitro treatment with IL-1ß potentiated oxytocin (OT)-induced myometrial contractility in the rat [29]. In these studies, the decidua was specifically removed before treatment; damage to cellular constituents in the intervening stromal regions and elimination of significant numbers of resident macrophages in endometrium could have reduced the concentrations of uterotonins or blocked paracrine interactions. These considerations may be essential for increased amplitude of uterine contractility and enhanced responsiveness to OT that occur before onset of parturition [30]. To assess the role of resident macrophages on spontaneous and agonist-induced contractility, the present study tested the hypothesis that inflammatory mediators regulate contractile activity by the intact gravid murine uterus near term.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Animals

C3H/HeN mice were obtained from Harlan Sprague Dawley (Indianapolis, IN). Time-dated pregnant mice arrived in the vivarium on Day 12 postmating. Mice were housed individually in plastic cages on a 12L:12D cycle (lights-on 0600 h); food and water were provided ad libitum. Mice were killed by cervical dislocation on the morning of Gestational Day 15 (between 0600 and 0700 h), 4 days prior to parturition. This day of pregnancy was chosen as the model for study because, compared to virgin mice, the uterus is characteristically in a quiescent phase of contractile activity, treatment with endotoxin induces preterm birth, and macrophages are more numerous than at other times of pregnancy [3, 14, 30]. The research protocol was reviewed and approved by the Institutional Animal Care and Use Committee.

Uterine Contractile Activity

Uterine contractile activity was assessed as previously described [30, 31]. Strips (2 x 5 mm) were cut from the middle regions of each uterine horn. Care was taken to insure that the endometrium remained intact on the myometrial strips. Ten uterine strips were obtained from each gravid uterus. Each strip was longitudinally mounted on a calibrated isometric transducer in a standard muscle bath preparation that contained 5 ml of oxygenated Na+-Krebs buffer at pH 7.4 and 37°C. Tissues were prepared during the first hour and equilibrated to approximately 1 g tension for the initial baseline recording. The time course of uterine contractile activity before and after treatment was assessed over a 4-h period (Fig. 1). An event consisted of 200 records, each a recording of current grams of tension every 2 sec over a 6.67-min period beginning at the time of specified treatment. The contractile response to OT (Bachem, Torrance, CA) was assessed after a 10-8.8 M dose of OT was added to each incubation chamber (EC50 dose [30]). After exposure to OT, tissue was washed and reequilibrated for 10 min in Na+-Krebs buffer. Duplicate strips of tissue were then treated with an anti-inflammatory cytokine, either IL-10 (10 ng/ml; Endogen, Woburn, MA), which is an inhibitor of macrophage activation, inflammatory cytokine production, and prostaglandin (PG) E2 production [32–34], or TGFß (10 ng/ml; R&D Systems, Minneapolis, MN), which is known to block IL-1ß-induced preterm delivery in mice [23]. To inhibit endogenous PG biosynthesis, a third set of uterine strips was treated with indomethacin (Indo, 10-5 M; Sigma, St. Louis, MO) [35, 36]. Doses were chosen based on published efficacy of treatments. After 7 min, LPS (10 µg/ml; Sigma) was added to the incubation solution. Thus, group designations are IL-10 + LPS, TGFß + LPS, and Indo + LPS, respectively. As a positive control, uterine strips that were initially treated with saline were given LPS, and a group given only incubation medium during the entire study served as a no-treatment negative control (Con). Contractile activity was recorded after addition of cytokines, Indo, or LPS and thereafter at hourly intervals. About 4 h after the onset of treatment, uterine strips were again challenged with OT. At the conclusion of the study, tissue was treated with 120 mM/L K+ to stimulate a maximal contractile response and confirm viability.



View larger version (53K):
[in this window]
[in a new window]
  		FIG. 1. Time course used to test the hypothesis that LPS-induced immune activation enhances uterine contractile activity. Insets are examples of in vitro spontaneous contractile activity of uterine strips from mice on Day 15 of pregnancy. For each event, 200 records were recorded over a 6.67-min period during baseline periods (events 1 and 3) and after OT challenge (events 2 and 10). Contractile activity was recorded immediately after administration of the anti-inflammatory reagents (event 4) IL-10 and TGFß or the administration of Indo. Recordings were made after LPS was added to the incubation chamber and at hourly intervals over the next 4 h (events 5–9). K+ challenge at the conclusion of the study confirmed viability of each strip of uterine tissue. Time line is set to visualize experimental protocol chronology rather than actual time scale

Data Analysis and Statistics

Contractile activity by each longitudinal uterine strip was analyzed in three ways. Total contractile force generated, i.e., integrated area, and frequency and amplitude of contractions were determined as previously described [30]. Automated mesurements were made with AcqKnowledge Software 3.5.7 (Biopac Systems, Santa Barbara, CA). A sensitivity threshold setting of 75% exceeded 95% coincidence compared with a randomized manual analysis of raw data. The area, amplitude, and frequency of contractile activity by duplicate uterine strips were averaged with respect to treatment period. Data were evaluated by one-way ANOVA (SPSS, Chicago, IL); outliers were excluded based upon stem and leaf analysis. When main effects were significant, individual comparisons were made using the least significant difference test (time course versus treatment) or Student t-test (OT challenge versus baseline effects). Differences were considered significant at P < 0.05. If the results of the Levene test for homogeneity of variance were significant, data were log transformed and reanalyzed. In a few instances, data were not normally distributed, in which case the nonparametric Kruskal-Wallis test with multiple comparisons was used.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Regular and repetitive contractions were demonstrated by every uterine strip throughout the study period (Fig. 1). Contractile activity of untreated uterine strips (i.e., only buffer solution in the bath) was unchanged throughout the baseline periods. Area, amplitude, and frequency of contractions were not significantly different over the 5-h study period (events 1, 3–9; ANOVA: P > 0.1, df = 7; data not shown).

Effects of LPS on Contractile Activity: Influence of Treatment with Cytokines or Indo

Treatment with LPS influenced some but not all aspects of uterine contractile activity. Following administration of LPS, neither frequency nor area of contractions was significantly different than those measures obtained during baseline periods (Fig. 2; data for area not shown). However, amplitude of contractions increased by 2 h after LPS treatment, an effect that was sustained for the duration of the study (events 1, 3, and 4 reduced compared with events 7–9; ANOVA: P < 0.002, df = 7).



View larger version (23K):
[in this window]
[in a new window]
  		FIG. 2. In vitro spontaneous contractile activity of uterine strips from mice on Day 15 of pregnancy. Data are the mean ± SEM (duplicate uterine strips from 5–7 mice) for amplitude (grams) or frequency of contractions/event (200 records of tension over the 6.67-min event) for the duration of the study. See Figure 1 for detailed chronology of treatment. Contractile activity during baseline events (1 and 3) served as controls to assess effects of administration just before event 4 ({triangledown}) of treatment with cytokine (IL-10, 10 ng/ml; TGFß, 10 ng/ml) or Indo (10-5 M). LPS ({blacktriangledown}, 10 µg/ml) was added immediately before event 5, and measurements were recorded at hourly intervals thereafter. Contractility by untreated uterine strips was unchanged throughout the entire study period (data not shown). Letters indicate a significant difference (P < 0.05) compared with event 1 (a), events 1 and 3–5 (b), or events 1, 3, 4, and 9 (c) of the same treatment group

Administration of anti-inflammatory cytokines did not block the ability of LPS to increase contractile activity. IL-10 or TGFß treatment alone did not influence any parameter of contractile activity (P > 0.05 for events 1 and 3 versus 4; Fig. 2, middle panels). For both cytokine treatment groups, as with the LPS group, neither area nor frequency of contractions demonstrated sustained differences compared with those values during baseline periods. However, amplitude of contractions after addition of LPS to uterine strips rose earlier in strips incubation with IL-10 or TGFß (P < 0.03, events 4 versus 7–9 for IL-10 or 6–9 for TGFß groups). Thus, the rise in contraction amplitude in the IL-10 or TGFß given LPS occurred 2 h and 1 h earlier, respectively, than it did in those uterine strips treated with LPS alone.

Indo did not alter baseline contractile activity, but it blocked the effects of LPS. A regular episodic waveform of contractions persisted over the 5-h study period. The area, amplitude, and frequency of contractions did not vary with respect to treatment with Indo or LPS (ANOVA: P > 0.1, df = 7).

Oxytocin Effects on Contractile Activity: Baseline and Treatment Responses

In controls, i.e., untreated tissue, OT treatments enhanced area (total integrated force), amplitude, and frequency of contractions relative to that during the initial baseline period. Comparison of events 1 and 2 (Fig. 3, left) indicated that OT induced a 2.1%, 1.58%, and 2.65% increase in contraction area, amplitude, and frequency, respectively, compared with baseline values (P < 0.0001, t = -4.75 to -12.0, df = 52–54). Replication of the OT challenge (event 10) produced a response similar to that in event 2 for area and frequency of contractions. However, a further increase in contraction amplitude of 38% between the initial and second OT treatment was evident (P < 0.005, t = -3.033, df = 30).



View larger version (57K):
[in this window]
[in a new window]
  		FIG. 3. Effect of OT on in vitro contractile activity of uterine strips from mice on Day 15 of pregnancy. Data are the mean (±SEM, duplicate strips for 5–7 mice) integrated area, amplitude, and frequency of contractions during a 6.67-min recording period at specified events. Left: Recordings for the initial baseline period (event 1) served as controls for those recordings made immediately after OTmax was added to the incubation chamber for events 2 or 10. Right: Contractile activity after administration of LPS to uterine strips treated with medium, IL-10, TGFß, or Indo as described in Figure 1 (event 10). Letters indicate a significant difference (P < 0.05) for comparisons with event 1 (a), or events 1 and 2 in Control group (b), or event 10 and all other LPS treatment groups (*)

LPS treatment did not affect the contractile response to OT by uterine strips (Fig. 3, right). Administration of OT increased area, amplitude, and frequency of contractions in tissue incubated for 4 h with LPS alone, an increase comparable to the OT response in untreated controls (event 10 versus 2, same treatment group; P > 0.06, t < -2, df = 12). Administration of LPS did not alter responsiveness to OT. Prior treatment with anti-inflammatory cytokines IL-10 or TGFß did not interfere with increased contractile activity induced by OT. By contrast, contraction amplitude in response to OT was significantly suppressed in tissue treated with Indo despite the presence of LPS for more than 3 h. Neither area nor frequency of contractions following OT challenge was suppressed by Indo treatment.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Enhanced amplitude of spontaneous uterine contractile activity following treatment with endotoxin suggests that an inflammatory promoter can facilitate spontaneous contractile activity by the pregnant murine uterus. As previously reported, few or no effects of LPS were apparent for area, i.e., integrated force, or frequency of contractions [28]. Endotoxin potentiated contractile amplitude by 2 h after treatment, and the increased amplitute was sustained for the 4-h study period (events 7–9). Focus on effects of endotoxin on amplitude rather than on frequency of contraction raises the possibility that endotoxin may act to synchronize myometrial activity rather than drive an endogenous pacemaker that initiates each contraction waveform. This effect parallels evidence that enhanced amplitude of myometrial contractions precedes onset of labor in mice [30]. Therefore, local coordination of powerful contractions rather than changes in frequency may be a common prerequisite for enhanced uterine contractility at term and in preterm labor.

LPS-enhanced amplitude of uterine contractions may underlie the ability of endotoxin, gram-negative infection, or related cytokines to induce premature labor and delivery in mice [3] and possibly in women [37, 38]. Preterm birth in women is, in a majority of cases, associated with microbial invasion of the chorion, amnion, endometrium, or placenta, with inflammatory cytokines in the amniotic fluid, or with premature rupture of fetal membranes [7, 39–42]. Resident phagocytes are the principal if not the only cell type in the female reproductive tract with a receptor-mediated signal transduction mechanism that is essential for immune responses to LPS [18, 43]. LPS is a membrane component of gram-negative bacteria that binds to TLR-4, a potent activator of monocytic phagocytes and macrophages [20, 44, 45]. Moreover, macrophages are a local source for PG production in the murine uterus [46] and are present in high numbers on Day 15 of pregnancy relative to their abundance in the peripartum period or in virgin mice [14, 18]. In the present study, the sustained increase in amplitude of spontaneous contractions following LPS treatment was likely related to a cascade of effects that results from enhanced local production of PGs within uterine strips [2]. This hypothesis is supported by the ability of Indo, an inhibitor of PG synthesis, to block LPS-induced increases in contraction amplitude.

To counter stimulation of contractile activity by LPS, uterine strips were treated with an anti-inflammatory cytokine to suppress macrophage activation. IL-10 and TGFß were used because these cytokines are endogenous inhibitors of other inflammatory cytokines and of PG production [33] and are implicated in processes of parturition [23, 47]. However, neither IL-10 nor TGFß treatment influenced baseline uterine contractile activity (event 4 versus event 3; Fig. 2) or blocked the ability of LPS to increase the amplitude of spontaneous contractions. The lack of effect of such anti-inflammatory treatments on LPS-induced contractile activity may reflect an influence of endotoxin that overrides amelioration by anti-inflammatory cytokines. Responsiveness by resident macrophages to cytokines may also depend upon dose, duration, or timing of anti-inflammatory treatments. In addition, absence of anti-inflammatory efficacy may reflect a paradoxical priming of leukocytes; in certain instances, IL-10 actually enhances the capacity of mononuclear phagocytes to produce inflammatory cytokines [48]. Amplitude of contractions in uterine strips treated with TGFß and LPS increased 1 h earlier than did those in tissue treated with LPS alone (event 6 versus event 7; Fig. 2). These considerations do not exclude the possibility that an appropriate anti-inflammatory treatment may block the influence of endotoxin on uterine contractility at this stage of pregnancy.

More macrophages are present in the murine uterus on Day 15 of pregnancy than in peripartum or nonpregnant mice, and a major proportion of these macrophages is already activated, i.e., express the intercellular adhesion molecule activation marker CD54 [14, 16]. Increased inducible nitric oxide synthase (iNOS) activity by resident macrophages may contribute to nitric oxide production and restrain uterine contractility [13, 49]. Suppressed myometrial contractility is associated with increased iNOS and high nitric oxide production in the uterus during pregnancy [50–52]. Overcoming this restraint may be related to local production of PGs. Macrophages have been suggested as an important source of PGs for uterine activity [21]. As potent agonists that promote contractile activity by the uterus, PGs or precursor treatments can initiate preterm labor throughout gestation. PGs stimulate phasic myometrial contractions by intracellular signaling pathways involving activation of phosphatidylinositol and the production of cytosolic calcium oscillations [53]. Thus, enhanced contractile activity following LPS-induced immune activation could be a consequence of increased cytokine and PG, along with decreased iNOS production. As recently reviewed by Romero et al. [54], functional genomic and proteomic studies have also implicated inflammatory processes in term and preterm parturition. The list of genes implicated includes IL-8, integrin{alpha}v, cytokine receptor EB13, and vascular endothelial growth factor receptor 1. Therefore, diverse evidence has implicated an immunological component to activation of processes in the pregnant uterus during premature labor and the initial phase of parturition.

The results of this study suggest that a local immune response to endotoxin activates increases in the amplitude of uterine contractions. Endotoxin did not interfere with the uterotonic effects of OT. As the principal cell population capable of responding to endotoxin in the pregnant murine uterus, macrophages may contribute to endotoxin-induced preterm labor. Attempts to preempt effects of LPS with IL-10 and TGFß were ineffective for a variety of reasons, but these findings do not exclude the possibility that resident macrophages may participate in the process through which endotoxin directly affects uterine contractility. More generally, increased uterine contractility appears to represent a local shift in uterine leukocyte activities that facilitate quiescence to stimulatory influences that promote synchronous and powerful contractions. These findings implicate an influence of immune cell activities in infection-related processes that may advance parturition.


   ACKNOWLEDGMENTS
 
The authors thank Long Tran for help in data acquisition, analysis, and preparation of graphs.


   FOOTNOTES
 
1 This project was supported in part by the Dean of the Loma Linda University School of Medicine. Back

2 Correspondence: Steven M. Yellon, Center for Perinatal Biology, Loma Linda University School of Medicine, Loma Linda, CA 92350. FAX: 909 558 4029; syellon{at}som.llu.edu Back

3 Present address: Department of Medical Services, Organon Pharmaceuticals, 375 Mt. Pleasant Ave., West Orange, NJ 07052 Back

Received: 17 January 2003.

First decision: 6 February 2003.

Accepted: 15 May 2003.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Dudley DJ. Immunoendocrinology of preterm labor: the link between corticotropin-releasing hormone and inflammation. Am J Obstet Gynecol 1999 180:S251-S256[CrossRef][Medline]
  2. Yellon SM, Mackler AM, Kirby MA. The role of leukocyte traffic and activation in parturition. J Soc Gynecol Invest 2003; (in press)
  3. Fidel PL Jr, Romero R, Wolf N, Cutright J, Ramirez M, Araneda H, Cotton DB. Systemic and local cytokine profiles in endotoxin-induced preterm parturition in mice. Am J Obstet Gynecol 1994 170:1467-1475[Medline]
  4. Dudley DJ. Pre-term labor: an intra-uterine inflammatory response syndrome?. J Reprod Immunol 1997 36:93-109[CrossRef][Medline]
  5. Romero R, Brody DT, Oyarzun E, Mazor M, Wu YK, Hobbins JC, Durum SK. Infection and labor. III. Interleukin-1: a signal for the onset of parturition. Am J Obstet Gynecol 1989 160:1117-1123[Medline]
  6. Romero R, Mazor M, Sepulveda W, Avila C, Copeland D, Williams J. Tumor necrosis factor in preterm and term labor. Am J Obstet Gynecol 1992 166:1576-1587[Medline]
  7. Romero R, Mazor M, Tartakovsky B. Systemic administration of interleukin-1 induces preterm parturition in mice. Am J Obstet Gynecol 1991 165:969-971[Medline]
  8. Romero R, Parvizi ST, Oyarzun E, Mazor M, Wu YK, Avila C, Athanassiadis AP, Mitchell MD. Amniotic fluid interleukin-1 in spontaneous labor at term. J Reprod Med 1990 35:235-238[Medline]
  9. Kluger MJ. Fever: role of pyrogens and cryogens. Physiol Rev 1991 71:93-127[Abstract]
  10. Saper CB, Breder CD. Endogenous pyrogens in the CNS: role in the febrile response. Prog Brain Res 1992 93:419-428[Medline]
  11. Dantzer R. Cytokine-induced sickness behavior: where do we stand?. Brain Behav Immunol 2001 15:7-24[CrossRef][Medline]
  12. Reid RR, Prodeus AP, Khan W, Hsu T, Rosen FS, Carroll MC. Endotoxin shock in antibody-deficient mice: unraveling the role of natural antibody and complement in the clearance of lipopolysaccharide. J Immunol 1997 159:970-975[Abstract]
  13. Hunt JS. Immunologically relevant cells in the uterus. Biol Reprod 1994 50:461-466[Abstract]
  14. Mackler AM, Iezza G, Akin MR, McMillan P, Yellon SM. Macrophage trafficking in the uterus and cervix precedes parturition in the mouse. Biol Reprod 1999 61:879-883[Abstract/Free Full Text]
  15. Sato TA, Gupta DK, Keelan JA, Marvin KW, Mitchell MD. Expression of interleukin-1beta mRNA in murine uterine and gestational tissues: relationship with gestational age. Am J Reprod Immunol 2001 46:413-419
  16. Mackler AM, Green LM, McMillan PJ, Yellon SM. Distribution and activation of uterine mononuclear phagocytes in peripartum endometrium and myometrium of the mouse. Biol Reprod 2000 62:1193-1200[Abstract/Free Full Text]
  17. Berlato C, Cassatella MA, Kinjyo I, Gatto L, Yoshimura A, Bazzoni F. Involvement of suppressor of cytokine signaling-3 as a mediator of the inhibitory effects of IL-10 on lipopolysaccharide-induced macrophage activation. J Immunol 2002 168:6404-6411[Abstract/Free Full Text]
  18. Grunwald U, Fan X, Jack RS, Workalemahu G, Kallies A, Stelter F, Schutt C. Monocytes can phagocytose gram-negative bacteria by a CD14-dependent mechanism. J Immunol 1996 157:4119-4125[Abstract]
  19. Wright SD, Tobias PS, Ulevitch RJ, Ramos RA. Lipopolysaccharide (LPS) binding protein opsonizes LPS-bearing particles for recognition by a novel receptor on macrophages. J Exp Med 1989 170:1231-1241[Abstract/Free Full Text]
  20. Akira S, Takeda K, Kaisho T. Toll-like receptors: critical proteins linking innate and acquired immunity. Nat Immunol 2001 2:675-680[CrossRef][Medline]
  21. Norwitz ER, Starkey PM, Lopez Bernal A, Turnbull AC. Identification by flow cytometry of the prostaglandin-producing cell populations of term human decidua. J Endocrinol 1991 131:327-334[Abstract]
  22. Steinborn A, von Gall C, Hildenbrand R, Stutte HJ, Kaufmann M. Identification of placental cytokine-producing cells in term and preterm labor. Obstet Gynecol 1998 91:329-335[Abstract]
  23. Bry K, Hallman M. Transforming growth factor-beta 2 prevents preterm delivery induced by interleukin-1 alpha and tumor necrosis factor-alpha in the rabbit. Am J Obstet Gynecol 1993 168:1318-1322[Medline]
  24. Abbas AK, Lichtman AH, Pober JS. Effector mechanisms of cell-mediated immunity. In: Cellular and Molecular Immunology, 4th ed. Philadelphia: W.B. Saunders; 2000:291–308
  25. Lim H, Paria BC, Das SK, Dinchuk JE, Langenbach R, Trzaskos JM, Dey SK. Multiple female reproductive failures in cyclooxygenase 2-deficient mice. Cell 1997 91:197-208[CrossRef][Medline]
  26. Tsuboi K, Iwane A, Nakazawa S, Sugimoto Y, Ichikawa A. Role of prostaglandin H2 synthase in murine parturition: study on ovariectomy-induced parturition in prostaglandin F receptor-deficient mice. Biol Reprod 2003; 69:195–201
  27. Gross G, Imamura T, Vogt SK, Wozniak DF, Nelson DM, Sadovsky Y, Muglia LJ. Inhibition of cyclooxygenase-2 prevents inflammation-mediated preterm labor in the mouse. Am J Physiol Regul Integr Comp Physiol 2000 278:R1415-R1423[Abstract/Free Full Text]
  28. Oshiro BT, Monga M, Eriksen NL, Graham JM, Weisbrodt NW, Blanco JD. Endotoxin, interleukin-1 beta, interleukin-6, or tumor necrosis factor-alpha do not acutely stimulate isolated murine myometrial contractile activity. Am J Obstet Gynecol 1993 169:1424-1427[Medline]
  29. Molnar M, Romero R, Hertelendy F. Interleukin-1 and tumor necrosis factor stimulate arachidonic acid release and phospholipid metabolism in human myometrial cells. Am J Obstet Gynecol 1993 169:825-829[Medline]
  30. Mackler AM, Ducsay CA, Veldhuis JD, Yellon SM. Maturation of spontaneous and agonist-induced uterine contractions in the peripartum mouse uterus. Biol Reprod 1999 61:873-878[Abstract/Free Full Text]
  31. Rhee JW, Longo LD, Pearce WJ, Bae NH, Valenzuela GJ, Ducsay CA. Effect of chronic hypoxia on myometrial responsiveness in the pregnant rat. Am J Physiol 1996 270:E477-E482
  32. D'Andrea A, Aste Amezaga M, Valiante NM, Ma X, Kubin M, Trinchieri G. Interleukin 10 (IL-10) inhibits human lymphocyte interferon gamma-production by suppressing natural killer cell stimulatory factor/IL-12 synthesis in accessory cells. J Exp Med 1993 178:1041-1048[Abstract/Free Full Text]
  33. Moore KW, Ho AS, Xu-Amano J. Molecular biology of interleukin-10 and its receptor. In: de Vries JE, de Waal Malefyt R (eds.), Interleukin-10. Austin, TX: REG Landes; 1995:1–10
  34. Hawkins DL, MacKay RJ, MacKay SL, Moldawer LL. Human interleukin 10 suppresses production of inflammatory mediators by LPS-stimulated equine peritoneal macrophages. Vet Immunol Immunopathol 1998 66:1-10[CrossRef][Medline]
  35. Clark DA, Banwatt D, Chaouat G. Effect of prostaglandin synthesis inhibitors on spontaneous and endotoxin-induced abortion in mice. J Reprod Immunol 1993 24:29-44[CrossRef][Medline]
  36. Kunkel SL, Wiggins RC, Chensue SW, Larrick J. Regulation of macrophage tumor necrosis factor production by prostaglandin E2. Biochem Biophys Res Commun 1986 137:404-410[CrossRef][Medline]
  37. Romero R, Emamian M, Wan M, Quintero R, Hobbins JC, Mitchell MD. Prostaglandin concentrations in amniotic fluid of women with intra-amniotic infection and preterm labor. Am J Obstet Gynecol 1987 157:1461-1467[Medline]
  38. Dinarello CA. Biology of interleukin 1. FASEB J 1988 2:108-115[Abstract]
  39. Iams JD, Johnson FF, Creasy RK. Prevention of preterm birth. Clin Obstet Gynecol 1988 31:599-615[CrossRef][Medline]
  40. Goldenberg RL. The management of preterm labor. Obstet Gynecol 2002 100:1020-1037[Abstract/Free Full Text]
  41. Romero R, Sirtori M, Oyarzun E, Avila C, Mazor M, Callahan R, Sabo V, Athanassiadis AP, Hobbins JC. Infection and labor. V. Prevalence, microbiology, and clinical significance of intraamniotic infection in women with preterm labor and intact membranes. Am J Obstet Gynecol 1989 161:817-824[Medline]
  42. Hebisch G. Cytokine levels in five different fluid compartments during amniotic fluid infection and labour. Adv Exp Med Biol 1997 433:87-90[Medline]
  43. Greenberg S, Grinstein S. Phagocytosis and innate immunity. Curr Opin Immunol 2002 14:136-145[CrossRef][Medline]
  44. Hetherington CJ, Kingsley PD, Crocicchio F, Zhang P, Rabin MS, Palis J, Zhang DE. Characterization of human endotoxin lipopolysaccharide receptor CD14 expression in transgenic mice. J Immunol 1999 162:503-509[Abstract/Free Full Text]
  45. Ghosh S, May MJ, Kopp EB. NF-kappa B and Rel proteins: evolutionarily conserved mediators of immune responses. Annu Rev Immunol 1998 16:225-260[CrossRef][Medline]
  46. Matthews CJ, Searle RF. The role of prostaglandins in the immunosuppressive effects of supernatants from adherent cells of murine decidual tissue. J Reprod Immunol 1987 12:109-124[CrossRef][Medline]
  47. Simpson KL, Keelan JA, Mitchell MD. Labor-associated changes in interleukin-10 production and its regulation by immunomodulators in human choriodecidua. J Clin Endocrinol Metab 1998 83:4332-4337[Abstract/Free Full Text]
  48. Adib-Conquy M, Petit AF, Marie C, Fitting C, Cavaillon JM. Paradoxical priming effects of IL-10 on cytokine production. Int Immunol 1999 11:689-698[Abstract/Free Full Text]
  49. Dong YL, Fang L, Gangula PR, Yallampalli C. Regulation of inducible nitric oxide synthase messenger ribonucleic acid expression in pregnant rat uterus. Biol Reprod 1998 59:933-940[Abstract/Free Full Text]
  50. Buhimschi I, Ali M, Jain V, Chwalisz K, Garfield RE. Differential regulation of nitric oxide in the rat uterus and cervix during pregnancy and labour. Hum Reprod 1996 11:1755-1766[Abstract/Free Full Text]
  51. Hunt JS, Miller L, Vassmer D, Croy BA. Expression of the inducible nitric oxide synthase gene in mouse uterine leukocytes and potential relationships with uterine function during pregnancy. Biol Reprod 1997 57:827-836[Abstract]
  52. Chwalisz K, Garfield RE. Role of nitric oxide in the uterus and cervix: implications for the management of labor. J Perinat Med 1998 26:448-457[Medline]
  53. Phillippe M, Saunders T, Basa A. Intracellular mechanisms underlying prostaglandin F2alpha-stimulated phasic myometrial contractions. Am J Physiol 1997 273:E665-E673
  54. Romero R, Kuivaniemi H, Tromp G. Functional genomics and proteomics in term and preterm parturition. J Clin Endocrinol Metab 2002; 187:2431–2434



This article has been cited by other articles:


Home page
 Reproductive SciencesHome page
A. S.-Y. Leong, J. E. Norman, and R. Smith
Vascular and Myometrial Changes in the Human Uterus at Term
Reproductive Sciences, January 1, 2008; 15(1): 59 - 65.
[Abstract] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
69/4/1165    most recent
biolreprod.103.015586v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Mackler, A. M.
Right arrow Articles by Yellon, S. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Mackler, A. M.
Right arrow Articles by Yellon, S. M.
Agricola
Right arrow Articles by Mackler, A. M.
Right arrow Articles by Yellon, S. M.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS