IL-23 Inhibits Trophoblast Proliferation, Migration, and EMT via Activating p38 MAPK Signaling Pathway to Promote Recurrent Spontaneous Abortion

Abstract

Recurrent spontaneous abortion (RSA), defined as the loss of ≥2 consecutive pregnancies before the 24th gestational week, affects 1%-2% women during their reproductive age [1]. As a common condition in reproductive medicine, RSA is reported in 1-2% of fertile couples seeking pregnancy and inflicts a significant physical, emotional, and financial burden on many families [2]. Many factors are thought to contribute to RSA, such as parental chromosomal abnormalities, maternal thrombophilia, immune dysfunction, and various endocrine disorders [3]. In addition, the age of the pregnant mother has also been reported to be a strong independent risk factor for miscarriage, and in particular, the risk of fetal miscarriage greatly increases after 35 years of age [4]. However, in many cases, the causes of RSA could not be easily identified, while the evidence-based diagnostic and treatment strategies are in short supply and the prospects of treatment are not as promising as they could be [5].Interleukin 23 (IL-23), which is composed of a p40 subunit and a specific p19 subunit, belongs to the IL-12 cytokine family and is secreted by dendritic cells and macrophages [6,7]. Accumulated reports have confirmed that IL-23 participates in the development of some autoimmune inflammatory diseases, including psoriasis, arthritis, and inflammatory bowel disease, thus serving as a critical therapeutic target for the improvement of inflammatory diseases [8][9][10]. In addition, another study reported that IL-23 was upregulated in patients with RSA [11]. Moreover, both IL-17 and IL-23 were verified to inhibit Langerhans cell (LC) migration in a psoriasis As a vital problem in reproductive health, recurrent spontaneous abortion (RSA) affects about 1% of women. We performed this study with an aim to explore the molecular mechanism of interleukin-23 (IL-23) and find optimal or effective methods to improve RSA. First, ELISA was applied to evaluate the expressions of IL-23 and its receptor in HTR-8/SVneo cells after IL-23 treatment. CCK-8, TUNEL, wound healing and transwell assays were employed to assess the proliferation, apoptosis, migration and invasion of HTR-8/SVneo cells, respectively. Additionally, the expressions of apoptosis-, migration-, epithelial-mesenchymal transition-(EMT-) and p38 MAPK signaling pathway-related proteins were measured by western blotting. To further investigate the relationship between IL-23 and p38 MAPK signaling pathway, HTR-8/SVneo cells were treated for 1 h with p38 MAPK inhibitor SB239063, followed by a series of cellular experiments on proliferation, apoptosis, migration and invasion, as aforementioned. The results showed that IL-23 and its receptors were greatly elevated in IL-23-treated HTR-8/SVneo cells. Additionally, IL-23 demonstrated suppressive effects on the proliferation, apoptosis, migration, invasion and EMT of IL-23-treated HTR-8/SVneo cells. More importantly, the molecular mechanism of IL-23 was revealed in this study; that is to say, IL-23 inhibited the proliferation, apoptosis, migration, invas...

Identification of chromosomal abnormalities in miscarriages by CNV-Seq

“…The following KEGG pathways were accurately related to miscarriages: MAPK signaling pathway, NF-κB signaling pathway, focal adhesion, and HIF-1 signaling pathway. Activating the p38/MAPK signaling pathway inhibits trophoblast proliferation, migration, and epithelial-mesenchymal transition (EMT), resulting in miscarriage [ 37 ]. Whereas blocking MAPK/ERK1/2 signaling pathway may inhibit the growth and invasiveness of human trophoblasts [ 38 ].…”

Atractylenolide promotes trophoblast cell proliferation and migration in recurrent spontaneous abortion via ERK pathway

“…The EMT is implicated in differentiation of trophoblast cells, and immune microenvironment of maternal-fetal interface [13]. Suppression of EMT of HTR-8/Svneo has been reported to promote progression of RSA [14]. The TGF-β1induced invasion, migration, and EMT of small intestine epithelial cells were repressed by atractylenolide III [15].…”

Exosome‐delivered miR‐410‐3p reverses epithelial‐mesenchymal transition, migration and invasion of trophoblasts in spontaneous abortion

“…Additionally, p38 MAPK can maintain pregnancy and promote labour, but its inappropriate activation can lead to adverse pregnancy outcomes 17 . Additionally, current research have shown that IL‐23 inhibits trophoblast proliferation, migration and EMT via activating p38 MAPK signalling pathway 18 . Hence, exploring the effects of miRNAs and the p38 MAPK signalling pathway is essential to study SA mechanisms.…”

“… 17 Additionally, current research have shown that IL‐23 inhibits trophoblast proliferation, migration and EMT via activating p38 MAPK signalling pathway. 18 Hence, exploring the effects of miRNAs and the p38 MAPK signalling pathway is essential to study SA mechanisms.…”