Increased placental expression and maternal serum levels of apoptosis-inducing TRAIL in recurrent miscarriage

Abstract

IntroductionRecurrent miscarriage (RM; ≥3 consecutive pregnancy losses) occurs in 1–3% of fertile couples. No biomarkers with high predictive value of threatening miscarriage have been identified. We aimed to profile whole-genome differential gene expression in RM placental tissue, and to determine the protein levels of identified loci in maternal sera in early pregnancy.MethodsGeneChips (Affymetrix®) were used for discovery and Taqman RT-qPCR assays for replication of mRNA expression in placentas from RM cases (n = 13) compared to uncomplicated pregnancies matched for gestational age (n = 23). Concentrations of soluble TRAIL (sTRAIL) and calprotectin in maternal serum in normal first trimester (n = 35) and failed pregnancies (early miscarriage, n = 18, late miscarriage, n = 4; tubal pregnancy, n = 11) were determined using ELISA.ResultsIn RM placentas 30 differentially expressed (with nominal P-value < 0.05) transcripts were identified. Significantly increased placental mRNA expression of TNF-related apoptosis-inducing ligand (TRAIL; P = 1.4 × 10−3; fold-change 1.68) and S100A8 (P = 7.9 × 10−4; fold-change 2.56) encoding for inflammatory marker calprotectin (S100A8/A9) was confirmed by RT-qPCR. When compared to normal first trimester pregnancy (sTRAIL 16.1 ± 1.6 pg/ml), significantly higher maternal serum concentration of sTRAIL was detected at the RM event (33.6 ± 4.3 pg/ml, P = 0.00027), and in pregnant women, who developed an unpredicted miscarriage 2–50 days after prospective serum sampling (28.5 ± 4.4 pg/ml, P = 0.039). Women with tubal pregnancy also exhibited elevated sTRAIL (30.5 ± 3.9 pg/ml, P = 0.035). Maternal serum levels of calprotectin were neither diagnostic nor prognostic to early pregnancy failures (P > 0.05).ConclusionsThe study indicated of sTRAIL as a potential predictive biomarker in maternal serum for early pregnancy complications.

RNA sequencing of chorionic villi from recurrent pregnancy loss patients reveals impaired function of basic nuclear and cellular machinery

“…Seminal microarray-based investigations of transcriptome and proteome of chorionic villi from RPL patients have demonstrated a dysregulated (mostly increased) expression of genes involved in regulating of immune function, apoptosis, angiogenesis and cytotrophoblast invasion1112495051. All these processes are also represented among the upregulated genes in our dataset (Fig.…”

“…The first study detected 133 genes showing a trend (fold change (fc) >2; nominal P -value < 0.05) for decreased and 22 genes for increased expression in the deciduas (maternal side of the placenta) of RPL patients compared to uncomplicated pregnancy11. The study by our team identified only 27 genes (fc, 1.4 to 4.1; P -value < 0.05) with a trend for altered expression in the RPL placental tissue12. Both reports highlighted an enrichment of dysregulated genes involved in cell communication and signalling, inflammatory and immune response.…”

Expression and Functional Characterization of NOD2 in Decidual Stromal Cells Isolated during the First Trimester of Pregnancy

“…In this study, we found MDP stimulation of NOD2 in DSCs significantly increased their apoptotic rate, which may be a contributing factor in spontaneous abortion [43]–[45]. However, further investigation is required to clarify the effect of MDP-induced apoptosis in DSCs on pregnancy outcome.…”

Decreased placental and maternal serum TRAIL-R2 levels are associated with placenta accreta

“…These studies are consistent with our study because we found significantly decreased TRAIL-R2 levels in the placental tissue and maternal serum of the accreta patients, suggesting a possible inverse relationship between TRAIL-R2 levels and trophoblast invasion. Additionally, according to the study of Rull et al, serum sTRAIL levels were higher in ectopic pregnancies and in uncomplicated pregnancies that subsequently terminated with an unexpected miscarriage; therefore, they suggest that serum sTRAIL levels are predictive for the forthcoming early pregnancy complications [26]. The study by Rull et al also showed that maternal serum sTRAIL levels are representative of the changes occurring within the placental tissue.…”

“…Agostinis et al recently showed that serum sTRAIL levels were significantly higher in patients with recurrent miscarriages compared with first-trimester normal pregnant women and suggested that TRAIL may have a pathogenic role in recurrent miscarriages by inhibiting the adhesion and migration capability of trophoblastic cells [25]. Similarly, Rull et al showed significantly increased placental mRNA expression of TRAIL and also significantly higher maternal serum sTRAIL in recurrent miscarriage patients [26]. These studies are consistent with our study because we found significantly decreased TRAIL-R2 levels in the placental tissue and maternal serum of the accreta patients, suggesting a possible inverse relationship between TRAIL-R2 levels and trophoblast invasion.…”