Molecular Human Reproduction, Vol. 8, No. 3, 281-285,
March 2002
© 2002 European Society of Human Reproduction and Embryology
Implantation and pregnancy |
The effects of a cytokine suppressive anti-inflammatory drug on the output of prostaglandin E2 and interleukin-1ß from human fetal membranes
Institute of Reproductive and Developmental Biology, Imperial College of Science, Technology and Medicine, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK
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Abstract |
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Fetal membranes are a primary source of prostaglandins and pro-inflammatory cytokines implicated in human parturition, so the inhibition of inflammatory pathways may be of benefit in pregnancies complicated by premature labour. We have therefore investigated the effects of a cytokine-suppressant anti-inflammatory drug (CSAID) on the output of prostaglandin E2 (PGE2) and interleukin (IL)-1ß from human fetal membranes in vitro. Bacterial endotoxin increased the expression of mRNA for IL-1ß and type-2 cyclo-oxygenase (COX-2), and there were corresponding increases in the output of IL-1ß protein and PGE2. The CSAID decreased IL-1ß protein, COX-2 expression and PGE2 output, but not mRNA for IL-1ß, indicating a post-translational effect on the production of IL-1ß and a transcriptional affect on COX-2, with an overall reduction in PGE2. These findings are consistent with the effects of CSAIDs in other systems, and indicate that they are of possible use in premature labour.
CSAID/fetal membranes/interleukin-1ß/labour/prostaglandin E2
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Introduction |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionAcknowledgementsReferences |
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Preterm labour is a major complication of human pregnancy, affecting 5–10% of all pregnancies each year. It is associated with 30% of long-term neonatal handicap, and 75% of perinatal deaths. The pathogenesis is incompletely understood at present, so it is difficult both to predict the onset of uterine contractions and cervical ripening, and to treat them effectively. The underlying biochemical pathways involved in the initiation of labour are not fully elucidated, although labour at all gestational ages strongly resembles an inflammatory reaction within the pregnant uterus (Mitchell, 1985
). There are global increases in a number of pro-inflammatory factors, including platelet-activating factor (PAF), cytokines [interleukins (IL)-1ß, -6, -8 and tumour necrosis factor (TNF)-
] and prostaglandins E2 and F2 (Romero et al., 1991, 1992, 1994; Santhanam et al., 1991; Toyoshima et al., 1995; Maymon et al., 1999), as well as increases in levels of proteolytic enzymes (Vadillo-Ortega et al., 1995). The latter may particularly be involved in cervical ripening and fetal membrane rupture. A series of studies have shown that co-ordinated changes in the levels of corticotrophin releasing hormone (CRH) and IL-1ß and -8, and in expression of type-2 cyclo-oxygenase (COX-2) enzyme and prostaglandin production occur before labour starts, and hence may be involved in the initiation of labour (McLean et al., 1995; Brown et al., 1998a; Slater et al., 1999; Elliott et al., 2001).
A number of studies indicate that the fetal membranes are important sources of prostaglandins and cytokines in human labour. Firstly, the output of these factors from fetal membranes is increased by labour (Dudley et al., 1996; Laham et al., 1996; Ammala et al., 1997; Slater et al., 1999). Furthermore, intact fetal membranes as well as cells isolated from amnion, chorion and decidua can produce cytokines and prostaglandins in vitro in response to stimuli (Mitchell et al., 1991, 1993; Dudley et al., 1992a,b, 1993). Many of the factors implicated in normal or abnormal human parturition (bacterial endotoxin, CRH, PAF, IL-1ß) can increase the output of these mediators from intact fetal membranes (Brown et al., 1998b; Rajasingam et al., 1998; Alvi et al., 1999a; Watari et al., 1999).
Pharmacological interventions in preterm labour have targeted myometrial contraction (ß-sympathomimetic compounds) and prostaglandin production [non-steroidal anti-inflammatory drugs (NSAIDs)]. Both classes of drugs have potentially damaging side-effects (Mari et al., 1990; Sawdy and Bennett, 1999), although more recent investigations with NSAIDs that show more specificity for the COX-2 are more promising (Groom et al., 2000). Furthermore, the effects of these treatments are very variable, and may be related to the nature of the therapeutic targets involved. As outlined above, changes in prostaglandin production and in myometrial contractility are not the only biochemical events in labour, so targeting a single pathway may not be effective.
The central roles of cytokines in the biochemistry of labour suggests that they may be potential targets for pharmacological interventions in preterm labour, as diminished cytokine levels or activity would be expected to decrease both prostaglandin production and proteolytic enzyme activity. A new family of drugs, the cytokine-suppressant anti-inflammatory drugs (CSAIDs), has been developed to inhibit cytokine-mediated events in vitro and in vivo. These compounds have a novel mechanism of action, in that they bind to the p38 mitogen-activated protein kinase [MAP kinase, which is also known as the cytokine suppresser binding protein (CSBP)], and thereby prevent its function (Lee and Young, 1996). This protein kinase is a critical point in the pathways associated with cytokines such as IL-1ß, and its inhibition will diminish the effects that IL-1ß has on other biochemical systems, as well as reduce the production of cytokines (Griswold et al., 1993).
A prototype compound of this type is SKF 86002, which decreases the production of IL-1ß from endotoxin-stimulated human macrophages (Perregaux et al., 1995), and also decreases COX-2 levels in leukaemic cells (Griswold et al., 1987). We have therefore determined the effects of the CSAID compound SKF 86002 [5-(4-pyridyl)-6-(4-fluorophenyl)-2,3-dihydroimidazo (2,1-b) thiazole] on the output of IL-1ß and PGE2 from intact human fetal membranes after stimulation with bacterial lipopolysaccharide (LPS).
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Materials and methods |
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The methods used in this study are essentially those described in our previous paper (Brown et al., 1998b
). The main features are given here.
Tissue collection and culture
Fetal membranes were collected from uncomplicated pregnancies at term (38–40 weeks gestation) after elective Caesarean section in the absence of labour or infection. Patients did not have pre-eclampsia and had not taken anti-inflammatory drugs prior to delivery. Ethics committee approval was obtained to use tissues which would normally be discarded. Tissues were washed with phosphate-buffered saline containing 10% penicillin, streptomycin and L-glutamine (Sigma, Poole, Dorset, UK). Disks of intact tissue (1.5 cm) were cut using a sharpened punch and cultured in Medium 199 supplemented with ITS (insulin, transferrin, selenium and linoleic acid all at 0.63 mg/ml, and bovine serum albumin at 0.13 mg/ml; Sigma) in multi-well tissue culture plates for 24 h at 37°C in an atmosphere of 5% CO2 and 95% air. After this time, the medium was changed and the tissue was incubated with fresh medium containing LPS (10 ng/ml) either alone or with SKF 86002 (10 µmol/l) (a gift from GlaxoSmithKline, Harlow, UK) for various time periods. The concentration of LPS was chosen on the basis of previous experience, and that of SKF 86002 on the basis of pilot experiments. These showed that 1 µmol/l SKF 86002 had limited effects, and that 100 µmol/l was no more effective than 10 µmol/l. The tissues were snap frozen in liquid nitrogen and stored at –80°C. The supernatants were then removed and frozen at –20°C until analysis for PGE2 and IL-1ß levels by enzyme-linked immunoassay (ELISA; Amersham Pharmacia Biotech, Amersham, Bucks, UK). The coefficients of variation were 7.5–8.1% (intra-assay) and 10.6% (inter-assay). Levels of PGE2 and IL-1ß were determined in at least five separate replicate experiments for each culture condition using tissues from at least five different women. Tissue viability was investigated with the diaphorase methodology (Aldred and Cooke, 1983); none of the additions had any effect.
RNA extraction and RT–PCR
Our earlier studies have shown that fetal membranes obtained at term by elective Caesarean section are not functionally homogenous (Brown et al., 1998a). About 50% of tissues are `non-activated', defined by low basal output of PGE2 which is increased by endotoxin, PAF or CRH; the other tissues are `activated', in that basal PGE2 output is high, and is not affected by endotoxin, PAF or CRH. For the mRNA expression analysis, we selected non-activated (responsive) tissues, identified by increases in PGE2 and IL-1ß output in response to LPS, as determined by ELISA (see above).
The selected fetal membrane discs were taken from three separate replicate experiments. Total RNA was extracted and stored at –80°C until use. The methods used for RNA extraction and RT–PCR analysis have been previously described (Brown et al., 1998b). RNA samples (1 µg) were used as the template for the production of cDNAs which were stored at –80°C until PCR amplification. The primers used for COX-2, IL-1ß and GAPDH have been reported previously (Slater et al., 1995; Alvi et al., 1999b). PCR was performed according to the manufacturer's method (Bioline, London, UK). Primer annealing temperatures were 58°C for GAPDH and COX-2 primers and 62°C for the IL-1ß primers. Cycle profiles were performed as described previously to ensure that the exponential phase was used to amplify the products. The cycle numbers chosen are indicated in the figure legends. Aliquots of the PCR products were separated by agarose gel electrophoresis and visualized under UV light.
To quantitate the PCR, 5 µl of each PCR reaction was dotted onto Hybond nylon filters. The filters were denatured, neutralized and washed and the DNA was fixed to the filters by UV crosslinking. Filters were first prehybridized for 1–2 h at 65°C followed by hybridization overnight with the appropriate 32P dCTP-labelled cDNA probe at 65°C. Excess probe was removed by washing in buffers of increasing stringency to 0.1 x sodium chloride/sodium citrate buffer (SSC). The levels of cDNA were then determined by ß-counting of the filter sections. The expression of each product was expressed as a ratio relative to the expression of GAPDH. The ratios were then represented as a fold increase or decrease in mRNA expression.
Statistical analysis
The results are shown as mean ± SEM. For statistical analysis, the results were log-transformed (because the raw data were not normally distributed) and investigated by repeated measures analysis of varience with post-hoc analysis with the Buonferroni correction (Statview 4.5 for Macintosh). Differences of P < 0.05 were considered to be significant.
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Results |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionAcknowledgementsReferences |
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The addition of LPS to cultured fetal membranes increased the output of PGE2 during 4–8 h of culture (Figure 1
), consistent with our previous studies. The inclusion of SKF 86002 decreased basal and LPS-stimulated PGE2 output at all time-points (Figure 1). The expression of COX-2 was investigated after 4 h of culture. LPS increased COX-2 expression 5.8 ± 2.8-fold compared with medium alone, and the inclusion of SKF 86002 completely inhibited the stimulation (0.9 ± 0.2-fold) (P < 0.05).
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), SKF 86002 (
), LPS (
) or LPS + SKF 86002 (
). All data are means ± SEM (n = 8). *P < 0.05 versus appropriate control (i.e. control for LPS + SKF 86002 is LPS alone).The output of IL-1ß from the same membranes was also determined, and LPS was found to increase IL-1ß levels (Figure 2
). The inclusion of SKF 86002 decreased both basal and LPS-stimulated levels of IL-1ß. The expression of IL-1ß mRNA was slightly increased in the presence of LPS (1.27 ± 0.10 versus control, i.e. medium alone), but this increase was not affected by SKF 86002 (1.34 ± 0.29 versus control).
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Discussion |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionAcknowledgementsReferences |
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SKF 86002 decreased the output of both IL-1ß and PGE2 from LPS-stimulated intact fetal membranes. It therefore seems that members of the CSAID group of compounds are potentially of use in the treatment of premature human parturition, as the production of at least two important factors involved in labour was affected.
It is apparent from previous studies that SKF 86002 has a post-translational inhibitory effect on the production of cytokines such as TNF-, IL-1ß and IL-6 (Griswold et al., 1993; Perregaux et al., 1995; Blanque et al., 1997). The reduced IL-1ß production and the lack of effect of SKF 86002 on mRNA for IL-1ß in the fetal membranes indicate that similar mechanisms may be operating in these tissues. These findings are consistent with the role of MAP kinase in the production of cytokines. The concentration of SKF 86002 used (10 µmol/l) was similar to that reported in other studies (Perregaux et al., 1995; Blanque et al., 1997), and the lack of tissue damage indicates a specific, rather than a toxic effect.
While the decrease in PGE2 output from fetal membranes is consistent with data from other systems, the precise mechanism is less easy to identify. Firstly, the decrease in production of IL-1ß could lead to loss of PGE2 output, as it is established that LPS-stimulated production of PGE2 is dependent on IL-1ß (Alvi et al., 1999b). This would indicate that the effects of SKF 86002 are mediated through the CSAID activity. Alternatively, SKF 86002 is also known to directly inhibit the activity of cyclo-oxygenase enzymes (Griswold et al., 1987), thus displaying a function similar to NSAIDs. Furthermore SKF 86002 not only inhibits the activity of COX-2 (Griswold et al., 1993; Pouliot et al., 1997), but this compound also decreases the expression of COX-2 mRNA (Pouliot et al., 1997). There are therefore three different mechanisms through which SKF 86002 could inhibit the production of PGE2 from fetal membranes (decreased IL-1ß output, decreased COX-2 expression or decreased COX-2 activity), but we cannot determine which is most important. Comparisons with other data show that some NSAIDs (flufenamic acid, nimesulide) can down-regulate the expression of COX-2 (Paik et al., 2000; Fahmi et al., 2001) as well as its activity, but this is not a general finding. Other NSAIDs (ibuprofen, indomethacin, naproxen, NS-398) have no effect on mRNA levels (Barrios-Rodiles et al., 1996; Stratman et al., 1997), whereas aspirin has no effect in human macrophages (Barrios-Rodiles et al., 1996), but up-regulates COX-2 mRNA in rat stomach (Davies et al., 1997). This indicates that these are complex effects which may be both tissue and species sensitive. In human fetal membranes, the reduced IL-1 production and reduced COX-2 expression probably contribute to the overall effect of SKF 86002, i.e. low production of PGE2. It is this reduced PGE2 production which is the primary endpoint of interest in considering any possible role for CSAIDs in treating preterm labour.
Finally, other work has strongly suggested that the induction of COX-2 in amnion cells and in other tissues is highly dependent on activation of nuclear factor 
B (NFB) (Allport et al., 2000; Lim et al., 2001), but this does not preclude the involvement of other signalling systems. In particular, there are a number of studies which suggest that p38 MAP kinase (CSBP) lies up-stream of NFB in the induction of COX-2 (Hwang et al., 1997; Chen et al., 1999) and iNOS (Chen et al., 1999) and in myocardial adaptation to ischaemia (Maulik et al., 1998). In all these studies, the interaction between p38 kinase and NFB is permissive rather than obligatory, such that inhibition of p38 MAP kinase activity does not completely abrogate NFB-mediated events. Furthermore, the activation of p38 MAP kinase alone does not induce the expression of COX-2 in a murine macrophage cell-line (Hwang et al., 1997), indicating that NFB is required. We cannot identify which mechanism or mechanisms are operating in intact fetal membranes, but the key finding remains that CSAIDs inhibit PGE2 output from human fetal membranes, and may thus have a role in tocolysis.
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Acknowledgements |
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We thank WellBeing (S.A.A.) and Action Research (N.L.B.) for their financial support of these studies. We are most grateful to GlaxoSmithKline for the generous provision of the CSAID SKF 86002. We gratefully acknowledge the assistance of Dr D.M.Slater in sub-cloning the probes used in this investigation.
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Notes |
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1 To whom correspondence should be addressed. E-mail: mark.sullivan{at}ic.ac.uk
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References |
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Submitted on August 9, 2001; resubmitted on October 3, 2001; accepted on December 14, 2001.
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