Abstract
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-α (TNF-α), interleukin-1β (IL-1β), 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-κB 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-κB and IL-6/STAT3 signaling pathway in the fetal membranes.
Highlights
Spontaneous preterm birth, occurring before 37 weeks of gestation, is a specific disorder of pregnancy
Human amniotic epithelial cells can be activated by external stimuli including lipopolysaccharide (LPS), hormone, and mechanical traction, and subsequently releasing a large number of inflammatory factors, such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6), which mediate the excessive inflammation associated with preterm birth [12, 13]
The results showed that IL-37 was significantly decreased in the peripheral blood plasma of Spontaneous preterm birth (sPTB) compared to term labor [0:89 ± 0:18 vs. 0:52 ± 0:04, t = 2:094, p = 0:046; (Figure 1(a))]
Summary
Spontaneous preterm birth (sPTB), occurring before 37 weeks of gestation, is a specific disorder of pregnancy. With around 15 million preterm infants born each year, accounting for approximately 10.6% of all live births worldwide, sPTB is considered to be the most frequent cause of mortality in neonatal and the second in children age below 5 years old worldwide [1, 2]. Those survived preterm neonates have higher rates of multiple complications, including neurological dysplasia, respiratory distress syndrome, neonatal pneumonia, necrotizing enterocolitis, and retinal disease, which cause a heavy burden to the family and society [3, 4]. Human amniotic epithelial cells can be activated by external stimuli including lipopolysaccharide (LPS), hormone, and mechanical traction, and subsequently releasing a large number of inflammatory factors, such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6), which mediate the excessive inflammation associated with preterm birth [12, 13]
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