Molecular Human Reproduction, Vol. 5, No. 9, 885,
September 1999
© 1999 European Society of Human Reproduction and Embryology
Molecular aspects of pregnancy |
Human placental cells show enhanced production of interleukin (IL)-8 in response to lipopolysaccharide (LPS), IL-1 and tumour necrosis factor (TNF)-
, but not to IL-6
1 Department of Obstetrics and Gynecology, Faculty of Medicine, Osaka University, 2–2 Yamada-oka, Suita City, Osaka 565-0871, 2 Department of Obstetrics and Gynecology, Osaka Police Hospital, 10–31 Kitayama-cho, Tennouji-ku, Osaka 543-8502, 3 Department of Obstetrics and Gynecology, Ikeda City Hospital, 3–1–18, Johnan, Ikeda City, Osaka 563-0025, and 4 Department of Gynecology, Osaka Medical Center for Cancer and Cardiovascular Diseases, 1–3–3 Nakamichi, Higashinari-ku, Osaka 537-0025, Japan
Abstract
Interleukin-8 (IL-8) is a chemotactic and activating factor for neutrophils which play important roles in host defence mechanisms. The human placenta constitutively produces IL-8 during pregnancy and enhances its production in chorioamnionitis. The present study was designed to investigate in vitro the regulatory mechanism for IL-8 production in the placentas in normal and inflammatory states. Placental cells produced IL-8 in a dose-dependent fashion when stimulated with lipopolysaccharide (LPS). The purified trophoblasts showed significantly higher IL-8 production than untreated placental cells. The expression of IL-8 gene in the trophoblasts in the third trimester was observed by reverse transcription–polymerase chain reaction (RT–PCR). The placental cells also release IL-8 in a dose-dependent manner, in response to r-(recombinant) IL-1
and tumour necrosis factor (TNF)-, but not rIL-6. Moreover, LPS-activated placental cells spontaneously produced a much larger amount of IL-8 and showed increased responses to rIL-1 and TNF-. It may, therefore, be proposed that placental cells with multiple endocrine functions exert immunological functions by constitutive production of IL-1 and TNF-, which stimulate placental IL-8 release. This cytokine cascade in the placenta may be augmented by LPS in chorioamnionitis, thereby potentiating the feto–maternal defence mechanisms against infection.
cytokine/IL-8/LPS/placental cell/trophoblast
Introduction
A central aspect in the initiation of inflammation is the extravasation and tissue infiltration of neutrophils (Baggiolini et al., 1989
). This process has been recognized as being mainly modulated by the compounds such as bacterial chemotactic peptide (Cassatella et al., 1992), platelet activating factor (Dewald and Baggiolini, 1986), leukotrien B4 (LTB4) (Samuelsson, 1983) and interleukin-8 (IL-8) (Matsushima et al., 1988). Among these compounds, IL-8 is one of the most potent chemotactic and activating factors for neutrophils, potentiating host defence mechanism against inflammation. IL-8 also stimulates T lymphocytes (Larsen et al., 1989) and activates basophils (Leonard et al., 1990). IL-8 is produced by a number of cells including human mononuclear cells (Schroder et al., 1987), endothelial cells (Schroder and Christophers, 1989), fibroblasts (Mielke et al., 1990) and mesothelial cells (Goodman et al., 1992). These cells actively produce IL-8 in response to exposure to IL-1, tumour necrosis factor- (TNF-), interferon-
(INF-), or lipopolysaccharide (LPS), forming the cytokine cascade among them (Matsushima et al., 1988; Goodman et al., 1992).
In perinatal infectious diseases, e.g. chorioamnionitis, neutrophils are the major leukocytes recruited at the feto–maternal interface and into the amniotic cavity (Romero and Mazor, 1988). Such neutrophil invasion might be triggered by IL-8 produced by organs at the fetomaternal interface. The placenta, with multiple endocrine functions, also plays an important role in feto–maternal defence mechanisms by constitutive production of IL-8 production in chorioamnionitis (Shimoya et al., 1992a). The placental IL-8 was immunohistochemically confirmed to be derived from trophoblasts and placental macrophages, Hofbauer cells (Shimoya et al., 1992a). Recently, it has been reported that IL-8 release was increased by LPS, IL-1 and TNF- from placental explants (Laham et al., 1997). Recently, it has been reported that chemokine expression, including IL-8 in human endometrium, coincided with leukocyte accumulation (Jones et al., 1997) and that interferon reduced the IL-8 secretion from endometrial stromal cells (Nasu et al., 1998). Although extensive studies have revealed the cellular and molecular mechanisms for IL-8 production by a number of cell populations including macrophage (Schroder et al., 1987), endothelial cells (Schroder and Christophers, 1989) and fibroblasts (Mielke et al., 1990), few studies have dealt with the mechanisms of IL-8 production by the cells in the human reproductive system such as placental cells, i.e. trophoblasts in normal and infected states. We have previously reported that monocyte chemotactic and activating factor (MCAF) was produced by placental cells with stimulation of LPS (Shimoya et al., 1998). Since LPS is often detectable in chorioamnionitis (Romero et al., 1987), our present study examined the nature of the cytokine cascade for placental IL-8 production by stimulation of placental cells with LPS. Our study established an in-vitro model for analysis of IL-8 production and release by placental cells in normal and infected states.
Materials and methods
Reagents
Human recombinant IL-1 (rIL-1) and TNF- were gifts from Dainippon Pharmaceutical Co. (Osaka, Japan). rIL-6 was kindly provided by Dr Kishimoto (Osaka University, Osaka, Japan). Lipopolysaccharide (LPS) was purchased from Sigma Chemical Co. (St Louis, MO, USA).
Preparation of single cell suspensions of placental cells and trophoblasts
Placental cells and trophoblasts were prepared from three different placentas. Single-cell suspensions were prepared as described previously (Shimoya et al., 1998). Briefly, placental blocks without labour and chorioamnionitis were incubated in 0.3 mg/ml DNase1 (Sigma) and 0.125% trypsin (Sigma) for 30 min, followed by application to a Percoll sedimentation gradient and centrifugation for 15 min at 200 g. The middle fractions which consisted of cytotrophoblast cells (80–85%) were resuspended in a 24-well flat-bottom plate (5x105 cells/ml per well) (Corning, Iwaki Glass, Tokyo, Japan). Cytotrophoblasts were identified as positive for cytokeratin by immunohistochemical staining. The viability of placental cells detected by Trypan Blue dye exclusion test was >90%. To further reduce the number of contaminating non-trophoblast cells, the suspensions were treated at 37°C for 30 min with appropriately diluted anti-human leukocyte antigen (HLA) class I monoclonal antibody (Dakopatts; Denmark) and anti-CD 14 monoclonal antibody (Becton-Dickinson; Mountain View, CA, USA) plus rabbit complement. The purity of trophoblasts was then examined by immunofluorescence analysis with anti-HLA class 1 and anti-CD14 monoclonal antibodies. Such treatment of placental cells remarkably reduced the number of the non-trophoblast cells such as HLA class 1+ cells from 20 to 3% and CD14+ cells from 6 to 1%. The purified trophoblasts (5x105 cells/ml) were resuspended and cultured in 24-well flat-bottom microplates (2 ml/well) (Corning).
Stimulation of placental cells with LPS
The placental cells (5x105/ml) were stimulated with various concentrations of LPS. The cell-free supernatants were collected after 2, 12, 24, 48, and 72 h of stimulation, filtered, and stored at –80°C until measurement of IL-8. We confirmed that IL-8 concentration of the culture medium was not affected by this filtration of supernatants.
Stimulation of trophoblasts with LPS
The trophoblasts (5x105/ml) were stimulated with various concentrations of LPS. The cell-free supernatants were collected after 48 h of stimulation, filtered, and stored at –80°C until measurement of IL-8.
Stimulation of normal and LPS-activated placental cells with rIL-1, rTNF- and IL-6
After 2 days of culture of placental cells in the presence or absence of 10 µg/ml LPS, the culture medium was removed. The cells were stimulated with either 20 ng/ml rIL-1, 200 ng/ml rTNF-, or 20 ng/ml rIL-6 for a time-course experiment. Normal and LPS-activated placental cells were also cultured in the presence of various concentrations of either rIL-1, rTNF-, or rIL-6 for 180 min to examine the dose-dependent effect of IL-1, TNF-, and IL-6 on IL-8 release. We confirmed that the concentrations of IL-1, TNF-, and IL-6 were not affected by the culture on plastic culture plates. The culture supernatants were collected, filtered, and stored at –80°C until titration of IL-8.
Preparation of peripheral blood mononuclear cells and stimulation with LPS
Heparinized peripheral blood cells were obtained from healthy volunteers, and monocytes were isolated by Ficoll–Hypaque gradient sedimentation. The monocytes were treated with anti-CD 14 monoclonal antibody plus rabbit complement for 30 min to eliminate contaminating macrophages. The treated and untreated responding cells (1x106/ml) were cultures in the presence or absence of various concentrations of LPS for 2 days. The cell-free culture supernatants were collected, filtered and stored at –80°C until titration.
IL-8 assay
For measurement of the IL-8 titre, an enzyme-linked immunosorbent assay (ELISA) kit specific for human IL-8 (R&D Systems, Minneapolis, USA) was used. The kit consistently detects IL-8 concentrations of >4.7 pg/ml. The kit is incapable of detecting other cytokines. The intra-assay and inter-assay variation of this kit were 5.4–9.2% and 7.3–12.2% respectively.
RNA extraction
RNA was extracted from trophoblasts using the acid guanidine thiocyanate–phenol–chloroform extraction method (Chomczynski and Sacchi, 1987).
Reverse transcription–polymerase chain reaction (RT–PCR) amplification
RT–PCR was performed using an RT–PCR high kit (Toyobo Co, Tokyo, Japan). The reaction was carried out in the presence of Maloney murine leuaemia virus (M-MLV) reverse transcriptase and 1 µl RNA sample in a 5x RT buffer, random primers, and dNTP mix for 40 min at 42°C. PCR amplification was performed, using an RT mixture (10 µl), with sequence-specific primers against human IL-8 (5'-ATGACTTCCAAGCTGGCCG-3'/5'-CTCAGCCCTCTTCAAAAACTT-3'). PCR was carried out for 35 cycles using a thermal cycler (Perkin Elmer/Cetus, Norwalk, CT, USA). Each cycle consisted of denaturation at 94°C (40 s), annealing at 52°C (40 s), and extension at 72°C (40 s). The amplification yielded a 273 bp DNA product (Shimoda et al., 1998). RT was performed with total RNA without reverse transcriptase (a mock RT sample) to detect genomic DNA contamination in RNA samples. A 20 µl sample of a 50 µl PCR mixture was electrophoresed on a 4% agarose gel and stained in ethidium bromide, and amplified products were visualized by UV illumination. Molecular sizes were estimated using a 100 bp DNA ladder. All primers were obtained from Becks (Tokyo, Japan).
Statistical analysis
Statistical analysis of experimental differences was performed by Student's t-test or Duncan's test. P < 0.05 was considered to be statistically significant. The values represent the means ± SEM of more than three independent experiments.
Results
To analyse in vitro the mechanism underlying the enhanced placental IL-8 production, we stimulated placental cells with LPS. Figure 1 shows that the difference in the IL-8 titre between LPS-stimulated and unstimulated placental cells became apparent as early as after 2 h of incubation (P < 0.01). The production of IL-8 by placental cells thereafter reached a plateau at 24 h. To examine the dose dependent effect of LPS on placental IL-8 production, the placental cells were cultured in the presence of various concentrations of LPS for 48 h. Figure 2 shows that placental cells produced IL-8 in an LPS-dose-dependent fashion, with maximal production at 10 µg/ml LPS.
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Placental cells contain various types of cells such as trophoblasts, placental macrophages, fibroblasts and endothelial cells (Douglas and King, 1989
). Since our immunohistochemical study demonstrated that trophoblasts are the major cells which produce IL-8 in the placenta (Shimoya et al., 1992a), we focused on the capacity and nature of the trophoblasts to produce IL-8. To obtain a purified trophoblasts fraction, we treated placental cells with anti-HLA class 1 and anti-CD 14 monoclonal antibodies plus rabbit complement. Such treatment of placental cells remarkably reduced the number of the non-trophoblast cells such as HLA class 1+ cells from 20 to 3% and CD14+ cells from 6 to 1%. As shown in Table I, the treated placental cells, i.e. purified trophoblasts, showed significantly higher IL-8 production than untreated placental cells. In contrast, similar treatment of peripheral monocytes with anti-CD14 monoclonal antibody plus complement caused a remarkable reduction in LPS-stimulated IL-8 production (Table II) and the number of CD14+ cells (from 6 to 1%). RT–PCR was performed to determine the expression of IL-8 gene in the trophoblasts. Figure 3 shows that IL-8 transcripts were present in the trophoblasts in the third trimester.
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In order to examine the regulatory mode of IL-8 production by human placental cells in normal and infected states, we first used rIL-1
to stimulate the normal and LPS-activated placental cells to release IL-8. As shown in Figure 4A, the normal placental cells stimulated by 20 ng/ml of rIL-1 released a significantly higher amount of IL-8 than the unstimulated normal placental cells during the culture time observed. The difference between these placental cells populations became apparent at 30 min after the start of culture (P < 0.05), and it became larger by further culture. For the LPS-activated placental cells, the difference between the rIL-1-stimulated and unstimulated groups became sharply apparent between 150 min (P < 0.05) and 180 min (P < 0.01). Compared with the normal placental cells, the LPS-activated placental cells released a higher amount of IL-8 in the presence of IL-1-mediated stimulation (2.8-fold at 180 min). Moreover, LPS-stimulated placental cells spontaneously release a higher amount of IL-8 (70-fold versus the control at 180 min), whereas the IL-8 titre produced by the normal placental cells remained low. In the experiment to test for a dose-dependent effect of IL-1 (Figure 4B), an enhancing effect of rIL-1 on normal placental cells was observed at 0.2 ng/ml (P < 0.01 versus the control) and reached a maximum at 2.0 ng/ml (P < 0.001 versus the control). LPS-activated placental cells produced a significantly higher amount of IL-8 at all the concentrations of rIL-1 tested compared with the normal placental cells, and the maximum production occurred at >20 ng/ml (Figure 4B).
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We then examined the kinetics of IL-8 release by normal and LPS-activated placental cells in the presence and absence of rTNF-
. The kinetics of rTNF--induced IL-8 release (Figure 5A) was quite similar to that of rIL-1-induced IL-8 release (Figure 4A
). The dose-dependent effect of rTNF- on IL-8 release from placental cells (Figure 5B) also showed a similar pattern to that of rIL-1 induced IL-8 release (Figure 4B).
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= LPS-activated placental cells stimulated with the control medium. 
= normal placental cells stimulated with TNF-
= normal placental cells stimulated with the control medium. (B) Both groups of placental cells were stimulated with various concentrations of TNF-Figures 6A and 6B
show the change in the amount of IL-8 released by normal and LPS-activated placental cells after the simultaneous addition of rIL-1 and rTNF-. With the normal placental cells an additive effect of suboptimal doses of rIL-1 and rTNF- was observed because placental cells stimulated by both cytokines released a consistently and significantly higher amount of IL-8 than placental cells stimulated by either cytokine alone (P < 0.05 versus rIL-1 or rTNF--stimulated trophoblasts) (Figure 6A). With the LPS-activated placental cells, however, no such additive effect was observed because placental cells stimulated by both cytokines failed to release a significantly higher amount of IL-8 than those stimulated by either cytokine alone.
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Since we had reported that IL-1 and TNF-
induce IL-6 release by normal human placental cells (Li et al., 1992), we examined whether IL-6 induced IL-8 release by placental cells. As demonstrated in Table III, stimulation of placental cells with rIL-6 failed to release IL-8, whereas rIL-1 and rTNF- induced IL-8 release. rIL-6-mediated stimulation of placental cells did not result in enhancement of IL-8 production (Table III). Even LPS-activated placental cells failed to release IL-8 in response to rIL-6 (data not shown).
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Discussion
We previously reported the constitutive production of IL-8 by human placenta during pregnancy (Shimoya et al., 1992a). Placental IL-8 production is enhanced by the presence of chorioamnionitis, but it is not modulated by labour (Shimoya et al., 1992a). Chorioamnionitis of the placenta also enhances the fetal serum IL-8 concentration (Shimoya et al., 1992b) by activating fetal immunocompetent monocytes to produce IL-8 (Taniguchi et al., 1992). Since IL-8 acts as a chemotactic and activating factor for neutrophils, which possess bactericidal action (Djeu et al., 1990), placental IL-8 may act as a mediator to recruit and accumulate neutrophils into the feto–maternal unit, thus potentiating the human reproductive systems defence mechanism against invading bacteria (Shimoya et al., 1992a). It has been reported that IL-8 release was increased by LPS, IL-1 and TNF- from placental explants (Laham et al., 1997). Although the regulatory mechanisms controlling the fetal IL-8 concentration have been studied (Taniguchi et al., 1992), the regulatory mechanisms controlling placental IL-8 productions have not been investigated.
Macrophages (Schroder et al., 1987) and endothelial cells (Schroder and Christophers, 1989) produce IL-8 in response to LPS as well as IL-1 and TNF- (LPS-responsive cells), whereas fibroblasts (Mielke et al., 1990) and mesothelial cells (Goodman et al., 1992) produce IL-8 in a inflammatory state only in response to IL-1 and TNF- which are derived from macrophages and endothelial cells, but not to LPS (cytokine-responsive cells). The amount of IL-8 produced is determined by mutual interactions between LPS responsive cells and cytokine-responsive cells. The trophoblast cell fraction enriched by Kliman's method (Kliman et al., 1986) still contains a certain number of Hofbauer cells, endothelial cells and fibroblasts (Shimoya et al., 1998). Therefore, it seems possible that LPS released by invading bacteria directly activates Hofbauer cells and endothelial cells in the placenta to produce IL-8: the activated cells simultaneously produce IL-1 and TNF-, and these cytokines then activate placental fibroblasts to produce IL-8. Placental IL-8 might be at least derived from these mixed cell populations of LPS-activated placental cells. Analysis of the activity of placental cells to produce IL-8 upon exposure to LPS would provide useful information on the regulatory mechanisms controlling IL-8 production by placentas with chorioamnionitis. Rat trophoblasts also express LPS-binding receptor having a molecular weight of 80 kDa (Hunt et al., 1989). Taken together, we concluded that trophoblasts themselves possess an LPS-responsive capacity to produce IL-8 as well as IL-1 and IL-1ß possibly by expressing LPS-binding receptor.
Treatment of peripheral monocytes with anti-CD14 monoclonal antibody plus complement resulted in a remarkable reduction in IL-8 production by LPS-mediated stimulation of monocytes as well as the cell number expressing CD14. That experiment suggested that such treatment of placental cells might be functionally effective in eliminating CD14+ cells. Indeed, similar treatment of placental cells with anti-CD14 and anti-HLA class 1 monoclonal antibodies plus complement remarkably reduced the number of CD14+ (Hofbauer cells) or HLA class 1+-expressing cells (endothelial cells and fibroblasts) (Kabawat et al., 1985). It seems, therefore, likely that LPS responsive cells such as macrophages and endothelial cell and cytokine-responsive cells like fibroblasts have been removed significantly. Nonetheless, the titre of IL-8 produced by the enriched trophoblast fraction was not impaired, but rather augmented after the treatment. Since trophoblasts express little HLA class 1 and no CD14 antigens (Kabawat et al., 1985), it is possible that trophoblasts were resultantly enriched by the treatment. Taken together, we concluded that trophoblasts themselves possess an LPS-responsive capacity to produce IL-8 as well as IL-1 and IL-1ß (Taniguch et al., 1991) possibly by expressing LPS-binding receptor.
IL-1 and TNF- share many biological activities including pyrogenicity (Dinarello et al., 1986), induction of IL-6 and human chorionic gonadotrophin (HCG) release from trophoblasts (Li et al., 1992; Masuhiro et al., 1991) as well as acute phase reactants (Le and Vilcek, 1987). IL-1 and TNF- also induce IL-8 production through IL-8 mRNA synthesis in a number of cell types such as monocytes (Leonard et al., 1990) and fibroblasts (Mielke et al., 1990). Furthermore, IL-1 and TNF--stimulated placental cells release IL-8 according to similar kinetics and magnitude. A study on signal transduction pathways for IL-8 production has demonstrated that IL-1 and TNF- as well as PMA activate a shared intracellular pathway by activating serine/threonine kinase to induce NFKB phosphorylation (Mahe et al., 1991). The phosphorylated NFKB translocates into the nucleus and binds to a regulatory region of the IL-8 gene with C/EBP, starting IL-8 mRNA synthesis (Mahe et al., 1991). Moreover, IL-1 and TNF- stimulation might stabilize IL-8 mRNA turnover and enhance IL-8 production because IL-1 stimulation is known to stabilize IL-8 mRNA and enhance IL-8 production in a human astrocytoma cell line (Kasahara et al., 1991). Such a regulatory signal transduction pathway might be operative in the promotion of IL-8 production by placental cells because the placental cells produce IL-1 (Taniguchi et al., 1991) and TNF- (Li et al., 1992) constitutively. These cytokines might collaboratively act on potentiation of the human reproductive system against infection.
Stimulation of placental cells with either rIL-1 or rTNF- resulted in IL-8 and IL-6 release, whereas stimulation of placental cells with rIL-6 did not induce any IL-8 release. A recent study (Nakajima and Wall, 1991) demonstrated an IL-6 and IL-6-receptor-mediated signalling pathway which did not possess any shared portions with the IL-1 and TNF--mediated signal transduction pathways for IL-8 release (Mahe et al., 1991). That might explain why IL-6-mediated stimulation of placental cells failed to induce IL-8 production. Consequently, placental cells-derived IL-1 and TNF- independently stimulate IL-8 and IL-6 releases from placental cells to regulate IL-8-dependent defence mechanisms and IL-6-dependent release of placental hormones, such as HCG (Li et al., 1992).
Neutrophil chemotactic activity may derive from many sources at various stages in the inflammatory responses, including macrophages which contribute NAP-1/IL-8 (Sylvester et al., 1990) and LTB4 (Martin et al., 1987), platelets which contribute NAP-2 (Walz and Baggiolini, 1990), monocytes which contribute NAP-1/IL-8 and melanoma growth-stimulating activity (MGSA/gro) (Schroder et al., 1990), and plasma exudation which contributes complement components. Other factors such as bacterial chemo- tactic peptide (N-formyl-methyonylleucylphenylalanine; FMLP) (Cassatella et al., 1992) and C5a formed by the complement activation process (Ember et al., 1992) also contribute collaboratively to the induction of neutrophil chemotactic responses to invading bacteria. Our present study has shown that placental cells, including trophoblasts, might contribute to the induction of such neutrophil infiltration in chorioamnionitis through LPS-induced enhancement of IL-8 production. When an initiating event (e.g. bacterial endotoxin release) takes place, it stimulates placental cells including trophoblasts, placental macrophages and fibroblasts to be activated and increases the amount of proinflammatory cytokines released into the utero–placental environment (Dinarello et al., 1986). The cytokines would further augment their IL-8 and other chemotactic factor production for the manifestation of chorioamnionitis to accumulate neutrophils at the fetomaternal interface (Romero and Mazor, 1988) and potentiate the defence mechanism of human reproductive organs.
Acknowledgments
This work was supported in part by Grants-in-Aid for Scientific research (Nos. 20151061, 30203897, 50294062, 70283786, 80301266 and 90093478) from the Ministry of Education, Science, and Culture of Japan (Tokyo, Japan).
Notes
5 To whom correspondence should be addressed at: Department of Obstetrics and Gynecology, Faculty of Medicine, Osaka University, 2–2 Yamada-oka, Suita City, Osaka 565-0871, Japan 
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Submitted on March 11, 1999; accepted on June 17, 1999.
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