Dataset Information

TAAR1 induces a disturbed GSK3β phosphorylation in recurrent miscarriages through the ODC.

ABSTRACT:

Objectives

Thyroid hormones play an important role in the maintenance of pregnancy. Their derivates, endogenous amines, act via binding to the trace amine-associated receptor (TAAR1). The aim of our study was to analyse the regulation of TAAR1, serine/threonine kinase (pGSK3β) and ornithine decarboxylase (ODC) in placentas of healthy pregnancies, spontaneous (SM) and recurrent miscarriages (RM) and to investigate the influence of thyroid hormone derivates on TAAR1 expression in trophoblast model cells in vitro.

Methods

Patients with SM (n = 15) and RM (n = 15) were compared with patients with healthy pregnancies (n = 15) (pregnancy weeks 7-13 each). Immunohistochemistry was applied to analyse placental TAAR1, pGSK3β and ODC expression. Protein expression of the receptors after stimulation with T₃, T₁AM and RO5203548 in BeWo trophoblast model cells was determined via Western blot. Double-immunofluorescence was used to determine placental expression of TAAR1 and ODC.

Results

Levels of TAAR1, pGSK3β and ODC were higher in placentas of RM in comparison to healthy controls. Stimulation of BeWo cells with T₃, T₁AM and RO5203548 significantly increased TAAR1 expression. ODC expression in BeWo cells was upregulated through T₃. Via double-immunofluorescence, TAAR1 and ODC-positive EVT could be detected.

Conclusions

Upregulation of placental TAAR1 may indicate an increased decarboxylation of thyroid hormones in miscarriages. Patients with RM may have a lack of T₃ through an enhanced transformation of T₃ into T₁AM induced by the ODC. Future investigations could be carried out to analyse what role a prophylactic T₃ substitution plays for patients.

SUBMITTER: Stavrou S

PROVIDER: S-EPMC5825928 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundWe recently demonstrated the increased abundance of anti-trophoblast antibodies (ATAB) in sera of patients with unexplained recurrent miscarriages (uRM). Further, the ATAB-positive sera bound to JEG-3 human choriocarcinoma cells in vitro, resulting in decreased productions of β-human chorionic gonadotropin (β-hCG) and progesterone in these cells. However, the specific antigenic epitopes of ATAB have remained unknown. Therefore, it was the aim of this study to determine specific targets of ATAB in uRM patients.MethodsPotential targets of ATAB were analyzed by 2-dimensional difference gel electrophoresis (2D-DIGE) and mass spectrometry, and thereby identifying α-Enolase (ENO1). ATAB targeting of ENO1 was further confirmed in a competitive binding assay. Levels of anti-ENO1 antibodies as well as β-hCG and progesterone were quantified with enzyme-linked immunosorbent assay (ELISA). Additionally, expression of ENO1 was analyzed in first trimester placentas by immunohistochemistry and immunofluorescence analysis.FindingsWe here identified ENO1 as a prominent target of ATAB. Serum levels of anti-ENO1 antibodies were increased in ATAB-positive compared to ATAB-negative patients. Further, increased expression of ENO1 and its co-expression with β-arrestin was found in the extra villous trophoblasts of uRM patients in first trimester placentas. In vitro, anti-ENO1 antibodies decreased the secretion of β-hCG and progesterone in JEG-3 and primary human villous trophoblast cells.InterpretationSerum anti-ENO1 antibodies might be an autoimmune biomarker for uRM. Targeting the formation of anti-ENO1 antibodies or inhibition of ENO1 expression could potentially represent therapeutic strategies for these patients. FUND: All authors declare no conflict of interest. Yao Ye was supported by the China Scholarship Council. Hellen Ishikawa-Ankerhold and Christian Schulz were supported by the SFB914, projects Z01 and A10. None of the rest authors has any conflict of interest to declare.