Increased expression of IFN-γ in preeclampsia impairs human trophoblast invasion via a SOCS1/JAK/STAT1 feedback loop

The weakening of extravillous trophoblast (EVT) invasion results in shallow placenta implantation. In HTR8/SVneo cells, IFN-gamma can activate STAT1 and reduce cell invasion, and suppressor of cytokine signaling (SOCS) is an important negative regulatory protein in the Janus kinase (JAK)/STAT activator pathway and has a negative feedback function on JAK/STAT1. The aim of the present study was to elucidate how SOCS1 feedback regulates JAK/STAT1 and affects EVT cell invasion, which in turn affects the development of preeclampsia (PE). MTT and Annexin V/phosphatidylserine (PS) assays were performed to evaluate the viability and apoptosis of HTR8/SVneo cells treated with IFN-gamma, respectively. Wound healing and invasion assays were also conducted to measure the migratory and invasive abilities of IFN-gamma-treated HTR8/SVneo cells. The mRNA and protein expression levels of genes were detected using reverse transcription-quantitative PCR and western blot analysis. Small interfering RNA knockdown of SOCS1 was used to verify the role of feedback regulation in the IFN-gamma-activated JAK/STAT1 signaling pathway. IFN-gamma can inhibit HTR8/SVneo migration and invasion, and promote apoptosis by increasing the expression of phosphorylated (p)-JAK, p-STAT1 and caspase3, and reducing the expression of platelet-derived growth factor receptor A and Ezrin. Furthermore, SOCS1 may negatively regulate JAK/STAT1 and affect HTR-8/SVneo invasiveness. Evaluation of clinical samples demonstrated that the expression levels of SOCS1 and IFN-gamma were higher in patients with PE compared with the healthy group. Collectively, the present results indicated that IFN-gamma reduced the invasion of HTR-8/SVneo cells by activating JAK/STAT1, concurrently leading to an increase in SOCS1, which negatively regulates JAK/STAT1 and eliminates the pro-inflammatory effects of IFN-gamma, thus forming a feedback loop.

Automated summary

This study investigated how SOCS1 feedback regulates JAK/STAT1 and affects EVT cell invasion, thereby impacting the development of PE. The findings revealed that IFN-gamma reduced the invasion of HTR-8/SVneo cells by activating JAK/STAT1, simultaneously increasing SOCS1 expression to counteract the pro-inflammatory effects of IFN-gamma.