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Original Article |
: Effect of 15-Deoxy-
12,14-PGJ2 and Troglitazone
Department of Obstetrics and Gynaecology, University of Melbourne, Mercy Perinatal Research Centre, Mercy Hospital for Women, East Melbourne, Victoria, Australia 3002
Address all correspondence and requests for reprints to: Martha Lappas, M.D., Department of Obstetrics and Gynecology, University of Melbourne, Mercy Hospital for Women, 126 Clarendon Street, East Melbourne 3002, Victoria, Australia. E-mail: mlappas{at}unimelb.edu.au.
Abstract
Peroxisome proliferator-activated receptor (PPAR)-
is a ligand-dependent nuclear receptor that is essential for murine placental development and trophoblast differentiation. In nonreproductive tissues, PPAR- regulates the formation of proinflammatory cytokines. Evidence suggests that many of the observed anti-inflammatory effects of PPAR- are in part caused by antagonizing the activities of the transcription factors, including nuclear factor-
B. The aim of this study was to elucidate whether natural [15-deoxy-
12,14-PGJ2 (15d-PGJ2)] and synthetic (troglitazone) PPAR- ligands regulate the secretion of IL-6, IL-8, and TNF-
from human intrauterine tissues. Human placenta, amnion, and choriodecidual tissues were incubated in the presence of 10 µg/ml lipopolysaccharide in the absence (control) or presence of 30 µM 15d-PGJ2 (n = 6 independent placenta) or troglitazone (n = 6 independent placentas). After a 6-h incubation, the incubation medium was collected and the release of IL-6, IL-8, and TNF- was quantified by ELISA. Treatment of placental, amnion, and choriodecidual tissues with both 15d-PGJ2 and troglitazone significantly reduced the release of lipopolysaccharide-stimulated IL-6, IL-8, and TNF- (t test, P < 0.05). Gel shift analyses demonstrated that 15d-PGJ2, but not troglitazone, suppressed nuclear factor-B DNA-binding activity. The data presented in this study demonstrate that the formation of proinflammatory mediators can be modulated by currently available therapeutic agents and may therefore be of therapeutic potential in human labor.
PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORS (PPARs) are a subset of the nuclear receptor superfamily that mediate diverse metabolic functions. PPAR activation, caused by ligand binding directly to the receptor, regulates the expression of genes involved in adipocyte proliferation, cell growth, and inflammation (1). There are three known isoforms of PPAR: PPAR-, PPAR-
(also known as PPAR-ß), and PPAR-, which carry out different physiological functions because of their diversity in tissue expression and ligand-binding specifications. In nongestational tissues, PPAR- has anti-inflammatory properties. Ligand activation down-regulates the formation of many proinflammatory mediators including the proinflammatory cytokines IL-6, IL-8, and TNF- (2, 3, 4, 5, 6, 7). In human intrauterine tissues, proinflammatory cytokines have been identified throughout human pregnancy and labor at the fetal-maternal interface and are thought to be particularly important in infection-associated preterm labor. Although PPAR- mRNA transcripts have been identified in human placenta, amnion, and choriodecidual tissues (8), its role in these tissues remains speculative. Therefore, the aim of this study was to determine whether PPAR- ligands decrease IL-6, IL-8, and TNF- release from human placenta, amnion, and choriodecidual tissues.
In the inactivated state, the PPAR forms a heterodimer with another nuclear receptor, retinoid X receptor (RXR), which has a high affinity for corepressor proteins, thereby preventing transcriptional activation by sequestration of the receptor complex from the promoter. PPAR- activation by ligand binding results in a conformational change to create a binding surface that has a high affinity for coactivators and a lower affinity for the corepressor. Once dissociation of the corepressors occurs, the activated heterodimer binds to the peroxisome proliferator response element (PPRE), with PPAR binding to the 5' half-site and RXR binding to the 3' half-site (9). PPREs consist of a direct repeat of the nuclear receptor hexameric DNA core recognition motif AGGTCA separated by one or two nucleotides. This results in either activation or suppression of transcription of target genes.
PPAR- is activated by a diverse range of both endogenous and exogenous ligands. Various eicosanoids act as ligands capable of activating PPAR- at low micromolar concentrations (10). PGD2, cyclopentenol of the prostanoid biosynthesis pathway, mediates PPAR- activation, with the most active terminal metabolite being 15-deoxy-12,14-PGJ2 (15d-PGJ2). Thiazolidinediones (TZDs) are synthetic compounds that bind and activate PPAR- with a high affinity (10). TZDs such as troglitazone, rosiglitazone (BRL49653), and pioglitazone are a class of antidiabetic drugs that were originally developed for the treatment of type 2 diabetes.
Ligation of PPAR is known to regulate transcription of target genes by at least three mechanisms. The first is classical nuclear receptor transcriptional activation, whereby ligand-bound PPAR binds to the PPRE site. This attracts cofactors and transcriptional proteins, and mRNA transcription of the target gene ensues. In the second, ligand-independent PPAR activity, direct protein:protein interaction of PPAR with other transcription factors, such as nuclear factor-B (NF-B), activator protein-1 (AP-1), and signal transducer and activator of transcription, or their coactivators interferes with these transcription factors to binding to their own response elements in target genes. The third is stoichiometric competition of PPAR and other transcription factors for RXR partners or for coactivators and corepressors. Evidence suggests that many of the observed anti-inflammatory effects of PPAR- are in part due to antagonizing the activities of the transcription factors NF-B, AP-1, and signal transducer and activator of transcription (2, 3, 4, 5, 6, 7).
Therefore, we hypothesized that ligation of PPAR- will reduce the secretion IL-6, IL-8, and TNF- from human gestational tissues, and these effects will in part be mediated through suppression of NF-B DNA-binding activity. Human placental, amnion, and choriodecidual tissues were incubated in the absence (control) or presence of two high affinity-specific PPAR- ligands, 15d-PGJ2 and troglitazone, and the release of proinflammatory cytokines into the incubation medium was quantified by ELISA.
Materials and Methods
Reagents
All chemicals were purchased from BDH Chemicals Australia (Melbourne, Victoria, Australia) unless otherwise stated. RPMI 1640 (phenol red free) was obtained from Life Technologies, Inc. (Grand Island, NY). BSA (RIA grade), dithiothreitol (DTT), EDTA, leupeptin, lipopolysaccharide (LPS) (from Escherichia coli 026:B6), ß-nicotinamide adenine dinucleotide hydroxide (disodium salt), 3,3',5,5'-tetramethylbenzidine, and pyruvic acid (dimer free) were supplied by Sigma (St. Louis, MO). Pefabloc SC (AEBSF) was purchased from Roche Molecular Biochemicals (Mannheim, Germany). The transcription factor consensus oligonucleotides for NF-B (5'-AGTTGAGGGGACTTTCCCAGGC-3') and AP-1 (5'-TTCCGGCTGACTCATCAAGCG-3'), HeLa scribe nuclear extract, gel shift-binding buffer, and polynucleotide kinase for labeling of 5'OH blunt-ended probes were purchased from Promega Corp. (Madison, WI). [-32P]dATP was purchased from Amersham Pharmacia Biotech (Buckinghamshire, England). Streptavidin-horseradish peroxidase conjugate and the IL-6, IL-8, and TNF- kits were supplied by Biosource Technologies, Inc. (Camarillo, CA). Troglitazone was generously provided by Sankyo Co., Ltd. (Tokyo, Japan) and 15d-PGJ2 was purchased from Cayman Chemical Co. (Ann Arbor, MI).
Tissue collection and preparation
Human placentae and attached fetal membranes were obtained (with Institutional Research and Ethics Committee approval) from women who delivered healthy, singleton infants at term (
37 wk gestation) undergoing elective cesarean section (indications for cesarean section were breech presentation and/or previous caesarean section). Tissues were obtained within 10 min of delivery, and dissected fragments were placed in ice-cold RPMI. Placental tissue was blunt dissected to remove visible connective tissue and calcium deposits. Choriodecidua was separated from amnion by blunt dissection and explants prepared by sharp dissection of 2.5-cm2 squares. Tissue fragments were placed in RPMI at 37 C in a humidified atmosphere of carbogen gas (95% O2 and 5% CO2) for 1 h. Explants were blotted dry on sterile filter paper and transferred to 24-well tissue culture plates (200–250 mg wet weight/well). The explants were incubated in duplicate in 2 ml RPMI containing penicillin G (100 U/ml) and streptomycin (100 µg/ml). Explant incubation was performed in the presence of 10 µg/ml LPS to achieve maximal cytokine release and NF-B activation.
Nuclear protein extraction
After the 6-h incubation, tissues were homogenized in 1:5 wt/vol Tris-buffered saline (150 mM NaCl and 50 mM Tris) by 3 x 20-sec bursts with a metal blade homogenizer (T25 Ultra-Turrax and S25N 8G dispersing tool, Janke and Kunkel GMBH and Co., Staufen, Germany). All subsequent steps were performed at 4 C. The homogenate was centrifuged at 1,200 x g for 10 min, and the supernatant was collected and stored at -20 C until assayed for protein content. The pellet was washed with 1 ml Tris-buffered saline, and centrifuged at 14,000 x g for 15 sec. The pellet was resuspended in 800 µl Buffer A [10 mM HEPES (pH 7.8), 10 mM KCl, 2 mM MgCl2, 0.1 mM EDTA, 1 mM DTT, 0.1 mM AEBSF, and 4 µg/ml leupeptin] and incubated for 15 min. Then 50 µl 10% Nonidet P-40 was added, and samples were vortexed for 30 sec and then centrifuged at 14,000 x g for 15 sec. The pellet was resuspended in 50 µl Buffer B [50 mM HEPES (pH 7.8), 50 mM KCl, 300 mM NaCl, 0.1 mM EDTA, 1 mM DTT, 1 mM AEBSF, 4 µg/ml leupeptin, and 1% glycerol], mixed gently for 20 min, and then centrifuged at 14,000 rpm for 5 min. The supernatant was collected and stored at -80 C. Protein concentration was determined using the BCA protein assay (Pierce Chemical Co., Rockford, IL), using BSA as a reference standard, as described below.
EMSA
The double-stranded NF-B oligonucleotide was end-labeled using T4 polynucleotide kinase and [-32P]ATP. The EMSA was performed using approximately 2 ng labeled NF-B oligonucleotide (20,000 dpm), 12 µg nuclear extract and 2 µl gel shift-binding buffer. The reactions were incubated at room temperature for 20 min, and 2.5 µl gel-loading buffer [250 mM Tris-HCl (pH 7.5), 0.2% bromophenol blue, and 40% glycerol] were added to each reaction. Complexes were resolved on a 4% polyacrylamide gel using 0.5X Tris-borate EDTA running buffer (90 mM Tris, 90 mM boric acid, and 2 mM EDTA) at 150 V for 3 h. After electrophoresis, the gel was dried and exposed to X-OMAT AR film (Kodak, New York, NY) overnight at -80 C. Autoradiographs were quantified using a GS-800 calibrated densitometer (Bio-Rad Laboratories, Inc., Richmond, CA) using Quantity One 4.2.1 analysis program. Data were corrected for background and expressed as OD/mm2.
Using supershift assays, previous studies in our laboratory have confirmed that the NF-B p50 and p65 heterodimers are activated in gestational tissues in response to LPS (Rice, G. E., manuscript in preparation). Antibodies to NF-B heterodimers p50 and p65 were added to nuclear protein extracts. Antibody binding resulted in a higher shift, or supershift, on EMSAs with a reciprocal decrease in the intensity of the NF-B band. Furthermore, the addition of both p50 and p65 antibodies eliminated the NF-B band. Antibodies to other Rel-related proteins, specifically C-Rel and p52, did not result in supershifts.
IL-6, IL-8, and TNF- ELISA
The concentration of IL-6, IL-8, and TNF- in the explant incubation medium was performed by sandwich ELISA (Biosource Technologies, Inc.) using monoclonal mouse IgG antibodies at a concentration of 0.5 µg/ml for capture and detecting antibody. The procedure was followed according to the manufacturer’s instructions. A benchmark microplate reader (Bio-Rad Laboratories, Inc.) was used to read the sample absorbance at 450 nm. The limit of detection of the IL-6, IL-8, and TNF- assays (defined as 2 SD from the zero standard) was 3, 2.8, and 7.2 pg/ml, respectively.
Tissue homogenate protein assay
The protein content of tissue supernatants was determined using the BCA protein assay (Pierce Chemical Co.), using BSA as a reference standard. Tissue supernatants were solubilized in 2 M sodium hydroxide (1:1 vol/vol) and boiled for 10 min. Then 1 M hydrochloric acid (1:1 vol/vol) was added to neutralize the sample. Samples were diluted in distilled water (1:2 vol/vol), and 10 µl of this sample was assayed for protein content.
Lactate dehydrogenase
To determine the effect of experimental treatments on cell membrane integrity, the release of the intracellular enzyme lactate dehydrogenase (LDH) into incubation medium was determined as described previously (11).
Statistical analysis
Statistical analyses were performed using a commercially available statistical software package (Statgraphics, STSC, Rockville, MD). Homogeneity of data was assessed by Bartlett’s test (12), and when significant, data were logarithmically transformed before further analysis. Two sample comparisons were analyzed using t test. Statistical difference was indicated by a P value of less than 0.05. Data are expressed as mean ± SEM of six different placental tissues.
Results
A human explant system was used to establish the effect of the PPAR- ligands 15d-PGJ2 and troglitazone on the release of IL-6, IL-8, and TNF- and NF-B DNA-binding activity from human gestational tissues. Placenta, amnion, and choriodecidual tissues were incubated in the absence or presence of 30 µM 15d-PGJ2 (n = 6 independent explants) and 30 µM troglitazone (n = 6 independent placentas). Following a 6-h incubation, tissues were collected and nuclear protein was immediately extracted and EMSA performed to determine NF-B DNA-binding activity. Incubation media was collected and assayed for IL-6, IL-8, and TNF- release by ELISA. Data represent the mean ± SEM. Significant differences, compared with control, are represented by P less than 0.05 (t test).
Validation of explant cultures and viability
To validate the integrity of explants in the presence of 15d-PGJ2 and troglitazone, cell viability was investigated using LDH release from explants. LDH release was investigated over the 6-h incubation period. Explants were incubated in either control medium (10 µg/ml LPS) or medium containing 30 µM 15d-PGJ2 or troglitazone. The effect of 15d-PGJ2 and troglitazone are detailed in Table 1
. Compared with the LPS control, treatment with 30 µM 15d-PGJ2 or troglitazone did not significantly affect LDH release from placenta, amnion, and choriodecidual tissues, indicating that the concentrations used did not affect cell viability.
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Secretion of IL-6 from placental, amnion, and choriodecidual tissue explants into the incubation medium was significantly decreased by 15d-PGJ2 (Fig. 1a). There was a 43-fold decrease in placenta, from 86.79 ± 24.87 to 2.01 ± 0.46 ng/mg protein; a 49-fold decrease in amnion, from 25.98 ± 8.85 to 0.53 ± 0.21 ng/mg protein; and a 23-fold decrease in choriodecidua from 89.70 ± 14.74 to 3.93 ± 0.38 ng/mg protein.
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). There was a 16-fold decrease in placenta, from 162.89 ± 31.62 to 9.94 ± 1.05 ng/mg protein; a 5-fold decrease in amnion, from 58.62 ± 14.07 to 12.29 ± 3.40 ng/mg protein; and a 10-fold decrease in choriodecidua from 147.00 ± 34.19 to 14.71 ± 2.12 ng/mg protein. Effect of 15d-PGJ2 and troglitazone on IL-8 release
Compared with LPS control, incubation of placental, amnion, and choriodecidual tissues with 15d-PGJ2 significantly attenuated the synthesis of IL-8 (Fig. 2a). There was a 16-fold decrease in placenta, from 40.47 ± 3.25 to 2.51 ± 0.69 ng/mg protein; a 16-fold decrease in amnion, from 17.94 ± 3.90 to 1.12 ± 0.57 ng/mg protein; and a 5-fold decrease in choriodecidua from 18.60 ± 1.76 to 3.55 ± 0.60 ng/mg protein.
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). There was a 3-fold decrease in placenta, from 33.35 ± 7.57 to 11.07 ± 3.05 ng/mg protein; a 4-fold decrease in amnion, from 39.00 ± 6.67 to 9.70 ± 3.34 ng/mg protein; and a 3-fold decrease in choriodecidua from 37.27 ± 8.33 to 12.96 ± 4.60 ng/mg protein.
Effect of 15d-PGJ2 and troglitazone on TNF- release
Secretion of TNF- from placental, amnion, and choriodecidual tissue explants into the incubation medium was significantly decreased by 15d-PGJ2 (Fig. 3a). There was a 10-fold decrease in placenta, from 3.15 ± 0.49 to 0.33 ± 0.08 ng/mg protein; a 67-fold decrease in amnion, from 7.42 ± 1.90 to 0.11 ± 0.05 ng/mg protein; and a 12-fold decrease in choriodecidua, from 14.91 ± 1.92 to 1.22 ± 0.27 ng/mg protein.
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from placental, amnion, and choriodecidual tissue explants into the incubation medium was significantly decreased by troglitazone (Fig. 3b). There was an 11-fold decrease in placenta, from 4.00 ± 0.82 to 0.36 ± 0.09 ng/mg protein; an 8-fold decrease in amnion, from 6.40 ± 1.75 to 0.78 ± 0.15 ng/mg protein; and a 4-fold decrease in choriodecidua, from 13.25 ± 2.96 to 3.47 ± 0.64 ng/mg protein.
Effect of PPAR- ligands on NF-B DNA-binding activity
Previous studies within our laboratory have demonstrated increased NF-B DNA-binding activity in nuclear extracts of human gestational tissues incubated with 10 µg/ml LPS (Rice, G. E., unpublished observations). Thus, in this study, to achieve maximal NF-B DNA-binding activity, all experiments were performed in the presence of 10 µg/ml LPS. The specificity of NF-B DNA binding was confirmed in competition experiments. Incubation with an excess of an unrelated oligonucleotide spanning AP-1-binding site did not antagonize NF-B binding (Fig. 4, lane 4), whereas competition with excess unlabeled NF-B oligonucleotide inhibited binding activity (Fig. 4, lane 3). Negative and positive (Fig. 4, lanes 1 and 2, respectively) controls were run in parallel.
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B in the regulation of cytokine production in human gestational tissues, it was first necessary to determine NF-B DNA-binding activity in nuclear extracts from these tissues. Figure 4 is a representative gel illustrating the detection of NF-B activation in nuclear extracts prepared from placenta (lane 5), amnion (lane 6), and choriodecidua (lane 7).
Treatment with 15d-PGJ2 significantly suppressed NF-B DNA-binding activity in nuclear extracts prepared from both amnion and choriodecidua (Fig. 5a). Compared with LPS control, there was a 2-fold decrease in NF-B DNA-binding activity from amnion (from 29.5 ± 5.9 to 11.1 ± 1.5 arbitrary units) and choriodecidua (from 110.1 ± 4.8 to 67.3 ± 15.7 arbitrary units). Troglitazone, on the other hand, had no significant effect on NF-B DNA-binding activity from either amnion or choriodecidua (Fig. 5b).
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PPAR- is a ligand-activated nuclear receptor that has recently aroused interest because of its anti-inflammatory properties. Troglitazone and 15d-PGJ2 are two PPAR- ligands that inhibit the production of proinflammatory cytokines from a number of test systems by antagonizing the activity of transcription factors, including NF-B (2, 3, 4, 5, 6, 7). These cytokines have been implicated in the initiation and progression of human labor and delivery, particularly in the setting of infection-associated preterm labor (13). Although PPAR- has been identified in human intrauterine tissues, whether PPAR- regulates cytokine formation by these tissues has yet to be evaluated. In this study, a human explant system was used to investigate the effects of 15d-PGJ2 and troglitazone on proinflammatory cytokine release from human placenta, amnion, and choriodecidual tissues.
A large number of PPAR- activators have been identified including natural ligands such as the eicosanoid 15d-PGJ2 and synthetic ligands such as troglitazone, an antidiabetic TZD drug (10). In this study, both 15d-PGJ2 and troglitazone, at 30 µM, significantly inhibited the release of IL-6, IL-8, and TNF- from human placental, amnion, and choriodecidual tissue explants.
The exact mechanism of the anti-inflammatory actions of PPAR- ligands remains controversial. The effects of TZDs and 15d-PGJ2 on inflammatory processes do not always display concordance, suggesting that at least one type of ligand, suggested to be 15d-PGJ2, acts independently of PPAR-. There is now evidence to suggest that 15d-PGJ2 interferes with the action of other transcription factors, including the NF-B signaling pathway. NF-B is a transcription factor that we have shown to be important for the formation of IL-6, IL-8, and TNF- from human placenta, amnion, and choriodecidual tissues (14). In this study, 15d-PGJ2, but not troglitazone, suppressed NF-B DNA-binding activity from all three tissues.
Recently a number of studies have identified PPAR- mRNA and protein in human gestational tissues and cells. PPAR- mRNA has been identified in JEG-3 cells and JAR choriocarcinoma cell lines (8, 15), invasive human cytotrophoblast nuclei in vivo, and trophoblasts and fetal endothelial cells in vitro (16). PPAR- has also been detected in human placenta, amnion (sporadic expression), and choriodecidua from term tissues, although no difference in PPAR- mRNA expression was detected from tissues obtained after spontaneous labor or elective cesarean section (8). Furthermore, studies in mice by Barak et al. (17) demonstrate that PPAR- is essential for normal placental development.
In addition to its roles in regulating the formation of putative uterotonic agents, PPAR- also appears to play a role in the initiation of apoptosis. Gestational tissues undergo terminal remodeling in preparation for parturition, which involves increased apoptosis toward term, a process that can also occur prematurely in the presence of infection or in intrauterine growth retardation-complicated pregnancies. Induction of apoptosis has indeed been reported in JEG-3 choriocarcinoma cells (15), WISH amnion cells (18), and the BeWo trophoblast cell line (19) in response to 15d-PGJ2; however, whether this is mediated through PPAR--dependent mechanisms has yet to be established.
It has yet to be established whether placenta, amnion, or choriodecidual tissues synthesize 15d-PGJ2. Mitchell et al. (20) demonstrated that placenta is a source of PGD2, and it has been demonstrated that estrogen stimulates both the conversion of PGD2 to 12-PGJ2 and PPAR- mediated increases in gene expression, albeit of the uropygial gland in the duck (21). Moreover, in the rat uterus, PGD2 levels decrease when the levels of estrogen are high (22). Thus, reduced levels of PGD2 may be due to increased PGD2 metabolism. This suggests that it is possible for regulated isomerization of PGD2 to PGJ2 metabolites to occur in some cells in response to specific stimuli. If PPAR--mediated gene expression is induced by estrogen in human gestational tissues, it could shed new light on the process of human labor. In support of this hypothesis, Waite et al. (16) demonstrated that placental PPAR- expression and activation is up- regulated by pregnancy serum. It is, therefore, plausible that natural PPAR- ligands are present in the human gestational environment, thus supporting a role for PPAR--mediated effects in pregnancy processes.
The evidence presented above indicates that PPAR- may be an attractive candidate for therapeutic intervention in cases in which there is uncontrolled release of proinflammatory mediators, as is the case with infection-associated preterm labor. The observed anti-inflammatory activity exhibited by PPAR- ligands on proinflammatory cytokine synthesis in human gestational tissues would be expected to favor the maintenance of pregnancy. Therefore, the generation of prostaglandins in response to an inflammatory signal may thus act as autoregulators involved in the maintenance of human parturition. Further investigation of the role of PPAR- in pregnancy may afford new insights into new applications for existing drugs.
Acknowledgments
We gratefully acknowledge the assistance of the Clinical Research Midwives Lyn Tuttle, Angie Denning, and Val Bryant and the Obstetrics and Midwifery staff of the Mercy Hospital for Women for their cooperation.
Footnotes
Abbreviations: AEBSF, Pefabloc SC; AP-1, activator protein-1; 15d-PGJ2, 15-deoxy-12,14-PGJ2; DTT, dithiotheitol; LDH, lactate dehydrogenase; LPS, lipopolysaccharide; NF-B, nuclear factor-B; PPAR, peroxisome proliferator-activated receptor; PPRE, peroxisome proliferator response element; RXR, retinoid X receptor; TZD, thiazolidinedione.
Received April 22, 2002.
Accepted July 7, 2002.
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