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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 12 6029-6033
Copyright © 2003 by The Endocrine Society

Other Original Article

Platelet-Activating Factor Inhibits the Secretion of Platelet-Activating Factor Acetylhydrolase by Human Decidual Macrophages

Hisashi Narahara, Yasushi Kawano, Kaei Nasu, Jun Yoshimatsu, John M. Johnston and Isao Miyakawa

Department of Obstetrics and Gynecology (H.N., Y.K., K.N., J.Y., I.M.), Oita Medical University, Hasama, Oita 879-5593, Japan; and Departments of Biochemistry and Obstetrics-Gynecology (J.M.J.), University of Texas Southwestern Medical Center, Dallas, Texas 75390-9038

Address all correspondence and requests for reprints to: Hisashi Narahara, M.D., Department of Obstetrics and Gynecology, Oita Medical University, 1-1 Idaigaoka, Hasama, Oita 879-5593, Japan. E-mail: naraharh{at}oita-med.ac.jp.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
To clarify the role of platelet-activating factor (PAF) in parturition, the effects of PAF on the secretion of PAF-acetylhydrolase (PAF-AH), a PAF-inactivating enzyme, by decidual macrophage populations were examined. The cells were isolated from human decidual tissue by enzymatic digestion, Ficoll-Paque centrifugation, or flow cytometric sorting. The nonhydrolyzable agonist of PAF, carbamyl-PAF (C-PAF), inhibited the secretion of PAF-AH by either decidual cells or flow cytometrically purified decidual macrophages. A specific PAF receptor antagonist, WEB 2086, blocked the C-PAF-induced inhibition. Lyso-PAF, a metabolite of PAF, had no effect on the enzyme secretion. An intracellular calcium channel blocker, bis-(o-aminophenoxy)-ethane-N,N,N',N'-tetraacetic acid, tetra(acetoxymethyl)-ester, partially blocked the inhibition by C-PAF, whereas extracellular calcium channel blockers, nifedipine and verapamil, were without effect. The inhibitory effect of C-PAF was also partially blocked by protein kinase C (PKC) inhibitors, sphingosine and H-7. A PKC activator, 12-O-tetradecanoylphobol 13-acetate, decreased the secretion of PAF-AH. The decrease was abolished by the addition of sphingosine and H-7. It is suggested that PAF inhibits the PAF-AH secretion by decidual macrophages and that the inhibitory action is mediated by a signal transduction mechanism involving intracellular calcium and PKC.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
PLATELET-ACTIVATING FACTOR (PAF; 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine) is the most potent proinflammatory lipid mediator described and is produced by various cell types including endothelial cells, platelets, neutrophils, and monocytes/macrophages (1). It has been suggested that PAF is involved in several diseases such as asthma, sepsis, cardiac infarction, cerebral ischemia, systemic hypertension, and gastric ulceration (2). In addition to these pathological conditions, PAF has also been implicated in a number of physiological processes, especially those of reproduction, including ovulation, sperm motility, implantation, fetal lung maturation, and the initiation and maintenance of parturition (3). We previously reported that increased quantities of PAF, possibly of fetal lung and kidney origin, are present in the amniotic fluid of women at term in labor (4). Nishihira et al. (5) confirmed this observation. PAF has been shown to stimulate prostaglandin E2 production in fetal membranes (6, 7) and cause human myometrial contraction (5, 8). PAF at concentrations as low as 10-12 M was reported to induce an increase in intracellular calcium and myosin light-chain phosphorylation in isolated human myometrial cells (8). We recently suggested a role for PAF in uterine cervical softening by the demonstration that PAF stimulated the expression of IL-8, monocyte chemoattractant protein-1, and matrix metalloproteinase-1 in human uterine cervical fibroblasts (9, 10).

Biological effects of PAF are thought to be receptor mediated. The PAF receptor was the first lipid receptor cloned, and its amino acid sequence was found to be similar to that of other guanine nucleotide regulatory protein (G protein)-coupled receptors (11). It is present on various cell types including smooth muscle cells, neutrophils, eosinphils, and monocytes/macrophages (12). PAF has been shown to enhance the release of newly synthesized PAF from human neutrophils via the G protein-coupled PAF receptor (13). It has become evident that a key event in PAF-mediated signaling mechanisms is the hydrolysis of phosphatidylinositol 4,5-bisphosphate, by a specific phospholipase C. One of the resulting second messengers, diacylglycerol, activates protein kinase C (PKC) whereas the second inositol 1,4,5-trisphosphate mobilizes intracellular calcium (12).

Inactivation of PAF is catalyzed by PAF-acetylhydrolase (PAF-AH), an active enzyme that removes the acetyl group from the sn-2 position and converts PAF into biologically inactive lyso-PAF (1). It has been reported that during the latter stages of pregnancy, PAF-AH activity decreased significantly in maternal plasma in several species (14). Cultured rat hepatocytes, HepG2 cells, human peripheral monocyte derived macrophages, and phorbol ester-stimulated HL-60 cells have been shown to secrete PAF-AH activity of the plasma type (1, 15). We previously demonstrated the secretion of the enzyme by human decidual macrophages and suggested the presence of autocrine or paracrine regulation of PAF concentration in the decidua (16). Endotoxins, proinflammatory cytokines such as IL-1ß and TNF{alpha}, and 1,25-dihydroxyvitamin D3 have been shown to inhibit PAF-AH secretion by human decidual macrophages (17, 18). We recently suggested a role for colony-stimulating factors (CSFs) in parturition. It was reported that granulocyte macrophage-CSF increases, whereas M-CSF decreases PAF concentration in the human decidua because of CSF-induced modulation of PAF-AH activity at the maternal-fetal interface (19).

To further clarify the role of PAF in parturition, we investigated the effects of PAF on the metabolism of PAF in the decidua. In the present study, the effects of carbamyl-PAF (C-PAF) (1-O-alkyl-2-N-methylcarbamyl-sn-glycero-3-phosphocholine), a nonhydrolyzable analog of PAF, on PAF-AH secretion by decidual macrophages has been examined as well as the possible mechanisms of signal transduction for PAF action.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Materials

Tritium-PAF (1-hexadecyl-2-[3H]acetyl-sn-glycero-3-phosphocholine, specific radioactivity = 10 mCi/µmol) was purchased from DuPont-NEN Life Science Products (Boston, MA). Unlabeled PAF was obtained from Avanti Polar Lipids (Phelman, AL) and purified by thin-layer chromatography on silica gel plates with a system containing chloroform:methanol:acetic acid:water (50:30:8:6) before use. Cell culture media, buffers, and supplements were purchased from GIBCO (Grand Island, NY), and bovine calf serum from HyClone (Logan, UT). Ficoll-Paque was obtained from Pharmacia (Piscataway, NJ). BSA (essentially fatty acid free), collagenase (type I), hyaluronidase (type I-S), deoxyribonuclease (type I), fluorescein-conjugated mouse monoclonal antibodies, WEB 2086, nifedipine, 12-O-tetradecanoylphobol 13-acetate (TPA), and 1-(5-isoquinolinesulfonyl)-2-metylpiperazine (H-7) were purchased from Sigma (St. Louis, MO). C-PAF, sphingosine, bis-(o-aminophenoxy)-ethane-N,N,N',N'-tetraacetic acid, tetra(acetoxymethyl)-ester (BAPTA/AM), and verapamil were obtained from Calbiochem (La Jolla, CA).

Cell preparation and culture conditions

Decidual tissue was obtained from patients at term and before the onset of labor after cesarean section. Cells were isolated by a modification of previously described methods (16). Briefly, after blood clots were removed, the decidual tissue was chopped into small pieces and suspended in Dulbecco’s PBS (D-PBS, minus Ca2+ and Mg2+, pH 7.4). The suspension was filtered through 70 µm nylon mesh to remove most of the associated blood cells, and the tissue remaining on the mesh was harvested. The tissue was incubated for 60 min at 37 C with a digestion medium consisting of Hanks’ balanced salt solutions containing collagenase (200 U/ml), hyaluronidase (1 mg/ml), deoxyribonuclease (150 µg/ml), 1% BSA, penicillin (100 U/ml), streptomycin (100 µg /ml), HEPES (20 mmol/liter), and sodium bicarbonate (30 mmol/liter). The cell digest was filtered through cotton gauze and 70 µm nylon mesh. Cells were washed with D-PBS, layered on a tube containing Ficoll-Paque (specific gravity 1.0788 ± 0.0025), and centrifuged for 30 min at room temperature (400 x g). Cells were recovered from the interface, washed with D-PBS, and cultured (2 x 105 cells/ml) with the specified additions in 24-well dishes in 1 ml of a complete medium consisting of Iscove’s modified Dulbecco’s medium containing 10% heat-inactivated bovine calf serum, penicillin (100 U/ml), streptomycin (100 µg/ml), HEPES (25 mmol/liter), sodium bicarbonate (40 mmol/liter), and L-glutamine (4 mmol/liter). The cultures were maintained in an atmosphere of 5% CO2/95% air at 37 C. After the indicated culture period, the medium was recovered, centrifuged at 10,000 x g for 5 min, and the supernatant was collected. The supernatant fluids were stored at -80 C until assayed. Viability was determined by trypan blue exclusion and the absence of lactate dehydrogenase release into the media. Cells were greater than 91% viable under all experimental conditions. The study had the approval of our Ethics Committee. Informed consent for the procedure was obtained from each patient.

Flow cytometry and sorting of pure cell populations

Antibody labeling, flow cytometry, and sorting of cells were carried out as described previously (16). For flow cytometric analysis, 1 x 106 cells were labeled with fluorescein-conjugated anti-CD14 mouse monoclonal antibody in 100 µl PBS (Ca2+ and Mg2+ plus, pH 7.4) containing 1% BSA for 30 min at 4 C. The cells were washed two times with 1 ml PBS containing 1.0% BSA by centrifugation at 3000 x g for 3 min in a microfuge. Subtype-matched fluorescein-conjugated mouse monoclonal antibodies unrelated to specific markers were used as a nonspecific control. Cells were analyzed in a flow cytometer (FACScan; Becton Dickinson, San Jose, CA). Dead cells were excluded from analysis based on propidium iodide staining and forward light scatter intensity. In some experiments, macrophages were further purified flow cytometrically using a flow cytometric cell sorter (FACStar). The data were analyzed with a Hewlett Packard series 300 computer (Portland, OR) with LYSIS-II software (Becton Dickinson).

PAF-AH assay

The activity of PAF-AH was assayed according to the method of Miwa et al. (20) with minor modifications. Tritium-labeled PAF and nonradiolabeled PAF were suspended in 0.1% BSA. A 0.05 mmol/liter final concentration of PAF was used in the assay tube. The assay mixture consisted of 0.3 ml of Tris-HCl (50 mmol/liter, pH 7.4) containing 0.2% BSA, various amounts of the diluted duplicate samples, and radiolabeled PAF substrate in a final volume of 0.5 ml. Standard serum samples from both a human and a rabbit source were assayed with each assay group. No significant change was noted in the standards throughout the study. The assay mixture was incubated for 20 min at 37 C. The reaction was terminated by addition of 0.5 ml of trichloroacetic acid (14% wt/vol) and the mixture centrifuged for 5 min at 4 C (600 x g). One tenth of a milliliter of the supernatant solution was removed and mixed with 5 ml of scintillation fluid (Budget-Solve; Research Products International Corp., Mount Prospect, IL). A unit of PAF-AH activity is defined as 1 nmol of acetate produced per hour at 37 C.

Statistical analysis

Means were compared by t test and ANOVA when appropriate. Values are reported as the mean ± SD. P < 0.05 was used as the definition of significance.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Digestion of term human decidua with collagenase, hyaluronidase, and deoxyribonuclease, followed by Ficoll-Paque density centrifugation yielded 13.6 ± 3.4 x 106 viable cells/g tissue (n = 32). Flow cytometric analysis indicated that 26 ± 5% of the cells were decidual macrophages (n = 5). C-PAF inhibited the PAF-AH secretion by the decidual macrophage populations in a dose-dependent manner (Fig. 1Go). The IC50 was 7.8 ± 0.6 x 10-9 mol/liter (n = 6). As shown in Fig. 2Go (n = 6), a specific PAF receptor antagonist, WEB 2086, blocked the PAF-induced inhibition (control, 182 ± 14 U/106 cells; C-PAF, 70 ± 6 U/106 cells, P < 0.001 vs. control; C-PAF plus WEB 2086, 167 ± 17 U/106 cells, P < 0.001 vs. C-PAF; WEB 2086, 204 ± 19 U/106 cells). Lyso-PAF, a metabolite of PAF, had no effect on the enzyme secretion (Fig. 2Go). C-PAF was without effect on proliferation of decidual cells (data not shown).



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  		FIG. 1. Effect of C-PAF on PAF-AH secretion by decidual macrophage populations. Cells were treated with various concentrations of C-PAF on d 0 and cultured for 6 d. PAF-AH activity in the medium was assayed. Results are expressed as percentage of the enzyme activity of a nontreated control.

 


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  		FIG. 2. Effects of C-PAF, WEB 2086, and/or lyso-PAF on PAF-AH secretion by decidual macrophage populations. Cells were treated with C-PAF (10-8 mol/liter), lyso-PAF (10-8 mol/liter), and/or WEB 2086 (10-5 mol/liter) on d 0 and cultured for 6 d. PAF-AH activity in the medium was assayed. Results are expressed as percentage of the enzyme activity of a nontreated control. *, P < 0.001 vs. control; **, P < 0.001 vs. C-PAF.

 
As indicated in Table 1Go (n = 4), the effect of C-PAF on the inhibition of the PAF-AH secretion by the cells was partially blocked by treatment of the culture with the PKC inhibitors, sphingosine and H-7 (control, 178 ± 13 U/106 cells; C-PAF, 64 ± 5 U/106 cells, P < 0.001 vs. control; C-PAF plus sphingosine, 104 ± 17 U/106 cells, P < 0.05 vs. C-PAF; C-PAF plus H-7, 103 ± 11 U/106 cells, P < 0.05 vs. C-PAF). An intracellular calcium channel blocker, BAPTA/AM, also partially blocked the C-PAF-induced inhibition of the enzyme secretion (C-PAF, 64 ± 5 U/106 cells; C-PAF plus BAPTA/AM, 91 ± 7 U/106 cells, P < 0.05 vs. C-PAF) (Table 1Go). In contrast, nifedipine and verapamil, calcium channel blockers that inhibit Ca2+ entry from the extracellular space, failed to prevent the PAF-induced inhibition of the enzyme secretion (C-PAF, 64 ± 5 U/106 cells; C-PAF plus nifedipine, 61 ± 4 U/106 cells; C-PAF plus verapamil, 53 ± 5 U/106 cells). Combination treatment with H-7 and BAPTA/AM showed additive blocking effect on the inhibition (C-PAF, 64 ± 5 U/106 cells; C-PAF plus H-7 plus BAPTA/AM, 135 ± 10 U/106 cells, P < 0.01 vs. C-PAF) (Table 1Go). Treatment with sphingosine, H-7, BAPTA/AM, nifedipine, or verapamil had no effect on the PAF-AH secretion in the absence of C-PAF (data not shown). A PKC activator, TPA, also decreased the PAF-AH secretion by the decidual cells. The inhibitory effect of TPA on the enzyme secretion was abolished by the presence of sphingosine or H-7 (control, 181 ± 15 U/106 cells; TPA, 56 ± 7 U/106 cells, P < 0.001 vs. control; TPA plus sphingosine, 185 ± 14 U/106 cells, P < 0.002 vs. TPA; TPA plus H-7, 154 ± 13 U/106 cells, P < 0.002 vs. TPA) (Table 1Go).


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  		TABLE 1. Effects of PKC inhibitors and/or calcium channel blockers on the C-PAF- or TPA-induced inhibition of PAF-AH secretion by human decidual macrophages

 
Flow cytometric sorting of cells isolated from decidual tissue by enzymatic digestion and Ficoll-Paque centrifugation yielded macrophage populations with 96 ± 3% purity (n = 3). The purified macrophages secreted PAF-AH into the culture medium, whereas nonmacrophage populations identified as CD14 negative did not secrete detectable amounts of the enzyme (data not shown). This observation confirms our previous findings that macrophages are the only cell type in the decidual cell populations that secrete PAF-AH (16). As shown in Table 2Go (n = 3), C-PAF inhibited the PAF-AH secretion by the purified macrophages (control, 502 ± 45 U/106 cells; C-PAF, 176 ± 21 U/106 cells, P < 0.001 vs. control), whereas lyso-PAF was without effect (lyso-PAF, 483 ± 62 U/106 cells). WEB 2086 blocked the inhibitory effect of C-PAF on the enzyme secretion by decidual macrophages purified flow cytometrically (C-PAF, 176 ± 31 U/106 cells; C-PAF plus WEB 2086, 429 ± 50 U/106 cells, P < 0.001 vs. C-PAF; WEB 2086, 521 ± 47 U/106 cells) (Table 2Go).


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  		TABLE 2. Effects of C-PAF, WEB 2086, and/or lyso-PAF on the PAF-AH secretion by human decidual macrophages purified flow cytometrically

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The activity of 1-O-alkyl-sn-glycero-3-phosphocholine acetyltansferase (acetyltransferase), a key regulatory enzyme that catalyzes the acetylation of lyso-PAF to form PAF, was present in human amnion, chorion, decidua, fetal lung, and fetal kidney (21). The acetyltransferase activity in human amnion tissue was stimulated markedly by Ca2+ at low concentrations (21). A similar Ca2+ activation for the acetyltransferase activity has been reported in human neutrophils (22). These findings suggest that PAF is produced in fetal membranes, lung, and kidney during parturition and that the autacoid production may be stimulated by Ca2+ concentrations in these tissues. We and others have suggested that the PAF concentration in tissues may also be regulated by the activity of PAF-AH (1, 3). It has previously been reported that during the latter stages of pregnancy, the activity of PAF-AH decreased significantly in the maternal plasma of the rat, rabbit, and human (3, 14). We considered that decidua may be the tissue site of the PAF-inactivation. PAF produced in the fetal and maternal compartments would be inactivated by maternal plasma PAF-AH because of its abundant blood supply, thus preventing PAF from reaching the myometrium. Besides the PAF inactivation by plasma PAF-AH in the decidua, we suggested a local regulatory mechanism that controls the autocrine or paracrine action of PAF, in which PAF-AH secreted by decidual macrophages may also play a pivotal role in the local concentration of PAF (16).

In the present study, it was demonstrated that C-PAF, a nonhydrolyzable analog of PAF, inhibited PAF-AH secretion by human decidual macrophages. A significant inhibition of the enzyme secretion was observed within the range of C-PAF that is similar to the reported concentrations of PAF in amniotic fluid and fetal membranes during term and preterm labor (4, 5, 23). The concentrations of C-PAF required to inhibit the secretion of PAF-AH were also compatible with that employed in the previous studies (9, 10, 22, 24, 25). WEB 2086, a specific PAF receptor antagonist, blocked the inhibitory effect of C-PAF on the secretion of PAF-AH by decidual macrophages, indicating that the PAF action was mediated by its specific receptors. It is suggested, therefore, that an increase in PAF in the human decidua, in association with the increase in PAF in amniotic fluid and fetal membranes during labor, may further elevate the concentration of PAF in the decidua because of its inhibitory effect on the PAF-AH secretion. The PAF-induced increase in the local concentration of PAF might also stimulate the production in amnion of other uterotonins such as prostaglandin E2 in amnion (6, 7), in addition to the direct stimulation by the autacoid on myometrial contraction (5, 8).

To date, little is known concerning the cellular interactions involved in the regulation of the PAF-AH secretion by decidual macrophages. Because it is well recognized that various cell types including monocytes/macrophages could be target cells for the action of PAF (1, 12), synergy between cell types with distinct functions should also be considered important in the induction of in vivo pathophysiological conditions during parturition. We addressed the interaction of macrophages with other cell types in the regulation of PAF metabolism. Because C-PAF inhibited the PAF-AH secretion by decidual macrophages purified flow cytometrically, it is most likely that the autacoid acts directly on the macrophages rather than indirectly via the action on the other cell types to inhibit the enzyme secretion.

The signal transduction pathway involving PAF in the regulation of PAF-AH secretion by decidual macrophages is yet to be elucidated. In several cell systems including monocytes/macrophages, it has been suggested that PAF stimulates membrane phosphoinositide turnover, generates inositol 1,4,5-trisphosphate and diacylglycerols, followed by an increase in intracellular calcium, leading to the activation of PKC (12). In the present study, BAPTA/AM partially blocked the inhibitory effect of C-PAF on the PAF-AH secretion by human decidual macrophages without affecting the enzyme secretion by itself. Therefore, intracellular Ca2+ mobilization may be, in part, responsible for the inhibition. On the other hand, nifedipine and verapamil failed to prevent the PAF-induced inhibition of the enzyme secretion. Accordingly, it does not appear that the Ca2+ entry from the extracellular compartment is important in the PAF-induced inhibition. The observation that sphingosine and H-7 also partially blocked the PAF-induced inhibition of PAF-AH secretion suggests the involvement of PKC activation in the inhibition of PAF-AH secretion. The combination treatment of intracellular Ca2+ channel blocker and PKC inhibitors resulted in an additive blocking of the PAF-induced inhibition, further suggesting that the autacoid action is dependent on the signals that antagonized by these blocking agents. Complementing these suggestions was the observation that TPA, a PKC activator, also inhibited the PAF-AH secretion by decidual macrophages. Taken together, these observations are consistent with a mechanism in which the PAF-induced inhibition is mediated by an intracellular calcium and PKC-dependent signal transduction. By analogy with these findings, it is suggested that bioactive molecules that increase intracellular calcium and activate PKC in decidual macrophages may elevate PAF concentration in the tissue by inhibiting the PAF-AH secretion.

In summary, we demonstrated that C-PAF inhibited the secretion of PAF-AH by human decidual macrophages. It is suggested that PAF may increase the local concentration of PAF in the decidua because of its inhibitory effect on the PAF-AH secretion by decidual macrophages, forming an autocrine or paracrine positive feedback loop at the maternal-fetal interface. The PAF action may be mediated, in part, by an intracellular calcium and PKC-dependent signal transduction mechanism. These observations provide further support for a central role of PAF in the periparturition events in the human.


   Footnotes
 
This work was supported, in part, by a Grant-in-Aid for Scientific Research (13671732) from the Ministry of Education, Science, and Culture of Japan.

Abbreviations: BAPTA/AM, Bis-(O-aminophenoxy)-ethane-N,N,N',N'-tetraacetic acid, tetra(acetoxymethyl)-ester; C-PAF, carbamyl-PAF; CSF, colony-stimulating factor; D-PBS, Dulbecco’s PBS; H-7, 1-(5-isoquinolinesulfonyl)-2-metylpiperazine; PAF, platelet-activating factor; PAF-AH, PAF-acetylhydrolase; PKC, protein kinase C; TPA, 12-O-tetradecanoylphobol 13-acetate.

Received April 21, 2003.

Accepted August 28, 2003.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals