IL-27 deficiency inhibits proliferation and invasion of trophoblasts via the SFRP2/Wnt/β-catenin pathway in fetal growth restriction

Abstract

Background: Fetal growth restriction (FGR) is characterized by restricted fetal growth and dysregulated placental development. The etiology and pathogenesis still remain elusive. IL-27 shows multiple roles in regulating various biological processes, however, how IL-27 involves in placentation in FGR pregnancy hasn't been demonstrated. Methods: The levels of IL-27 and IL-27RA in FGR and normal placentae were determined by immunohistochemistry, western blot and RT-PCR. HTR-8/SVneo cells and Il27ra -/-murine models have been adopted to evaluate the effects of IL-27 on the bio-functions of trophoblast cells. GO enrichment and GSEA analysis were performed to explore the underlying mechanism. Findings: IL-27 and IL-27RA was lowly expressed in FGR placentae and administration of IL-27 on HTR-8/SVneo could promote its proliferation, migration and invasion. Comparing with wildtypes, Il27ra -/embryos were smaller and lighter, and the placentae from which were poorly developed. In mechanism, the molecules of canonical Wnt/β-catenin pathway (CCND1, CMYC, SOX9) were downregulated in Il27ra -/placentae. In contrast, the expression of SFRP2 (negative regulator of Wnt) was increased. Overexpression of SFRP2 in vitro could impair trophoblast migration and invasion capacity.Interpretation: IL-27/IL-27RA negatively regulates SFRP2 to activate Wnt/β-catenin, and thus promotes migration and invasion of trophoblasts during pregnancy. However, IL-27 deficiency may contribute to the development of FGR by restricting the Wnt activity.

Association of IL‐17 and IL‐27 polymorphisms with susceptibility to recurrent pregnancy loss and pre‐eclampsia: A systematic review and meta‐analysis

“…While Jahantigh found a positive correlation between elevated IL‐27 levels and PE severity, 9 Yin's research showed no notable contrast in serum IL‐27 levels between the control and PE groups but noticed a surge in the expression of IL‐27 and its receptors in trophoblast cells in PE. 36 Additionally, Zhang found that IL‐27 can encourage the proliferation, migration, and invasion of trophoblast cells, 37 while Ge found that IL‐27 regulates the epithelial‐mesenchymal transition of trophoblast cells, thereby inhibiting their migratory and invasive capacity, and contributing to the pathogenesis of PE. 38 These discrepancies could be due to differences in sample size, time of onset of PE, and IL‐27 concentrations applied in in vitro experiments.…”

CPY27B1-related vitamin D deficiency contributes to the impaired function of CD4+T cells in Recurrent spontaneous miscarriage

“…Next, fresh complete medium was substituted for further cultivation. The infection efficiency was evaluated by Western blot 48 h after infection [ 16 ].…”

“…The PVDF membranes were incubated with primary antibodies against CYP27B1 (1:500, ab206655, abcam), β-catenin (1:500, Abcam, ab230169) or GAPDH (1:1000, ab75479, abcam) overnight at 4 °C respectively. Then PVDF membranes were washed with PBST solution three times and treated with peroxidase-conjugated goat anti-rabbit IgG secondary antibody (1:5000; Bioworld Technology, BS10003) or goat anti-mouse IgG secondary antibody (1:5000; Bioworld Technology, BS10003) at room temperature for 1 h. After adequate washing, Immobilon Western Chemiluminescent HRP Substrate Kit (Millipore, WBKLS0100) was used for chemiluminescence detection [ 16 ].…”