IL-37 Exerts Anti-Inflammatory Effects in Fetal Membranes of Spontaneous Preterm Birth via the NF-κB and IL-6/STAT3 Signaling Pathway

Abstract

<jats:p>Spontaneous preterm birth (sPTB), defined as delivery before 37 weeks of gestation, is thought to be a multifactorial syndrome. However, the inflammatory imbalance at the maternal-fetal interface promotes excessive secretion of inflammatory factors and induces apoptosis and degradation of the extracellular matrix (ECM), which can subsequently lead to preterm birth. As an anti-inflammatory molecule in the IL-1 family, interleukin-37 (IL-37) mainly plays an inhibiting role in a variety of inflammatory diseases. However, as a typical inflammatory disease, no previous studies have been carried out to explore the role of IL-37 in sPTB. In this study, a series of molecular biological experiments were performed in clinical samples and human amniotic epithelial cell line (Wistar Institute Susan Hayflick (WISH)) to investigate the deficiency role of IL-37 and the potential mechanism. Firstly, the results indicated that the expression of IL-37 in human peripheral plasma and fetal membranes was significantly decreased in the sPTB group. Afterward, it is proved that IL-37 could significantly suppress the production of tumor necrosis factor-<jats:italic>α</jats:italic> (TNF-<jats:italic>α</jats:italic>), interleukin-1<jats:italic>β</jats:italic> (IL-1<jats:italic>β</jats:italic>), and interleukin-6 (IL-6) in WISH cells. Simultaneously, once silence IL-37, LPS-induced apoptosis and activity of matrix metalloproteinases (MMPs) 2 and 9 were significantly increased. In addition, the western blot data showed that IL-37 performed its biological effects by inhibiting the NF-<jats:italic>κ</jats:italic>B and IL-6/STAT3 pathway. In conclusion, our results suggest that IL-37 limits excessive inflammation and subsequently inhibits ECM remodeling and apoptosis through the NF-<jats:italic>κ</jats:italic>B and IL-6/STAT3 signaling pathway in the fetal membranes.</jats:p>

Current Understanding of IL-37 in Human Health and Disease

“…Macrophage-expressed IL-37b reduces pro-inflammatory gene and protein expression upon various inflammatory stimuli relevant to atherosclerosis (36). However, knockdown of IL-37 significantly increased the LPS-induced inflammatory gene and protein expressions in WISH cells, which were reversed by administering recombinant human IL-37 (rhIL-37) (37). Similarly, administration of IL-37 neutralizing antibodies increases the production of inflammatory factors in LPS-Stimulated PBMCs (25).…”

“…The inflammatory imbalance at the maternal-fetal interface promotes the over-secretion of inflammatory factors by human amniotic epithelial cells, and induces apoptosis of human amniotic epithelial cells and extracellular matrix (ECM) degradation, leading to preterm birth. Human peripheral plasma and fetal membranes of sPTB show a decreased IL-37 expression (98). In addition, IL-37 inhibits the production of TNF-a, IL-1b, and IL-6 in WISH cells (98).…”

“…Human peripheral plasma and fetal membranes of sPTB show a decreased IL-37 expression (98). In addition, IL-37 inhibits the production of TNF-a, IL-1b, and IL-6 in WISH cells (98). IL-37 silencing significantly increases LPSinduced apoptosis and activity of MMP 2 and 9 in WISH cells (98).…”

“…In addition, IL-37 inhibits the production of TNF-a, IL-1b, and IL-6 in WISH cells (98). IL-37 silencing significantly increases LPSinduced apoptosis and activity of MMP 2 and 9 in WISH cells (98). Thus, IL-37 suppresses excessive inflammation, ECM remodeling, and apoptosis by the inhibition of TNF-a, IL-1b, and IL-6 in the cells of the fetal membrane (98).…”

NETs promote ROS production to induce human amniotic epithelial cell apoptosis via ERK1/2 signaling in spontaneous preterm birth

“…3 Pregnancy involves homeostasis between immune activation and immune tolerance, accompanied by a series of inflammatory factors and the generation and transformation of immune cells. 4,5 The maternal-fetal interface mainly comprises the placenta, fetal membrane, decidua, and uterus. However, the fetal membrane is composed of the amniotic membrane and chorionic membrane and is rich in the extracellular matrix (ECM), which plays a vital role in the pathophysiology of preterm labor.…”