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Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL), TRAIL Receptors, and the Soluble Receptor Osteoprotegerin in Human Gestational Membranes and Amniotic Fluid during Pregnancy and Labor at Term and Preterm

Liggins Institute (M.L., D.A., K.W.M., R.J.A.H., T.A.S., M.D.M., J.A.K.) and Department of Pharmacology and Clinical Pharmacology (M.D.M., J.A.K.), University of Auckland Faculty of Medical and Health Sciences, Auckland, New Zealand; Perinatology Research Branch, National Institute of Child Health and Human Development, National Institutes of Health/Department of Health and Human Services (T.C., R.R.), Detroit, Michigan 48201; and Perinatology Research Branch (T.C., R.R.), National Institute of Child Health and Human Development, National Institutes of Health/Department of Health and Human Services, Bethesda, Maryland 20892

Address all correspondence and requests for reprints to: Dr. Jeffrey A. Keelan, Liggins Institute, University of Auckland, Faculty of Medical and Health Sciences, 2–6 Park Avenue, Grafton, Auckland, New Zealand. E-mail: j.keelan{at}auckland.ac.nz.

We have studied TNF-related apoptosis-inducing ligand (TRAIL) and its membrane-bound (R1–R4) and soluble receptors [osteoprotegerin (OPG)] in gestational membranes to assess their significance in preterm parturition and premature rupture of membranes (PROM). TRAIL was detected by ELISA in extracts of term choriodecidual (but not amnion) tissues and explant-conditioned media. Concentrations of OPG (determined using ELISA) in gestational membranes were 20- to 50-fold greater than those of TRAIL. Median OPG concentrations in amniotic fluid (AF) at 15–17 wk gestation were similar to those at term before and during labor, whereas levels in pregnancies sampled preterm were significantly elevated. OPG levels in AF from women with preterm PROM were similar to those from women in preterm labor. In contrast, in pooled AF samples (n = 23–33), TRAIL concentrations at term with and without labor were elevated compared with samples from preterm deliveries. TRAIL-R3 and -R4 decoy receptors were detected in term amnion and choriodecidual extracts by immunoblotting and were localized by immunohistochemistry to amnion epithelial cells and chorionic trophoblasts. TRAIL (100 ng/ml) had little or no effect on amnion or choriodecidual cell viability or apoptosis, although these tissues responded to TNF- with increased prostaglandin E₂ production. Our findings suggest that OPG is abundant in gestational membranes and, in concert with TRAIL decoy receptors, may protect resident cells of the fetal membranes against the proapoptotic effects of TRAIL and other related ligands during pregnancy.

This work was supported by grants from the New Zealand Lottery Health Grants Board and the Health Research Council of New Zealand.

Abbreviations: AF, Amniotic fluid; BGG, bovine -globulin; BrdU, bromodeoxyuridine; LDH, lactate dehydrogenase; MIAC, microbial invasion of the amniotic cavity; MTT, 3-(4,5-dimethlythiazol-2-yl)-2,5-diphenyl tetrazolium bromide; NF-B, nuclear factor-B; OPG, osteoprotegerin; PGE₂, prostaglandin E₂; PPROM, preterm PROM; PROM, premature rupture of membranes; rh, recombinant human; TRAIL, TNF-related apoptosis-inducing ligand; TRAIL-R, TRAIL receptor.

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