IL-37 Exerts Anti-Inflammatory Effects in Fetal Membranes of Spontaneous Preterm Birth via the NF-κB and IL-6/STAT3 Signaling Pathway
Authors: Hanwen Zhang
Yuxin Ran
Nanlin Yin
Lulu Wang
Dongni Huang
Hongbo Qi
Zheng Liu
Jie He
Journal: Mediators of Inflammation (2020)
Discipline: IMMUNOLOGY
Keywords: sPTB; interleukin-37; inflammatory imbalance; maternal-fetal interface; apoptosis
Affiliations: Department of Obstetrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.

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. 

Retracted: No

PubPeer comments:
 This paper makes use of * human amniotic epithelial cell line (Wistar Institute Susan Hayflick (WISH)) * But as it is known since 1968 and confirmed in the 1980 s WISH is an HeLa contaminated cell line. How someone can still make use of WISH as a model of an amniotic cell line 52 years after it has been known to be contaminated is baffling. In this paper they have used WISH to study * anti-inflammatory effect of IL-37 in fetal membranes *. All the conclusions of this paper relevant to the experiments carried out on the WISH cell line are thus invalid. See the relevant [Cellosaurus entry] , 
 #1 In the case that the laboratory does not have the experimental technology to isolate primary human amniotic epithelial cells, the use of commercial cell lines is a reasonable choice. In recent years, many preterm labor studies have selected WISH cells to establish in vitro models. To a certain extent, it is feasible to complete some basic experiments with this cell line. For instance, Li et al have used the WISH cell line to investigate the induction of preterm premature rupture of membranes by inflammatory cytokines (TNF-u03b1, IL-6) [1-2]. Additionally, a study indicated that there are plenty of biomedical literature with important data on fundamental events that govern cell and molecular biology testified by using cell line. And in most instances, cross-contamination does not invalidate these findings[PMID:24520087]. Therefore, it seems reasonable and feasible to use WISH cell line for experiments. At least it can provide some limited new information in unknown areas. We only need to interpret the results carefully, and of course, further verification is needed. References [1]Li W, Zhao X, Li S, Chen X, Cui H, Chang Y, Zhang R. Upregulation of TNF-u03b1 and IL-6 induces preterm premature rupture of membranes by activation of ADAMTS-9 in embryonic membrane cells. Life Sci. 2020 Nov 1;260:118237. doi: 10.1016 j.lfs.2020.118237. Epub 2020 Aug 8. PMID: 32781068.21. [2]Yao JL, He QZ, Liu M, Chang XW, Wu JT, Duan T, Wang K. Effects of u0394(9)-tetrahydrocannabinol (THC) on human amniotic epithelial cell proliferation and migration. Toxicology. 2018 Feb 1;394:19-26. doi: 10.1016 j.tox.2017.11.016. Epub 2017 Nov 27. PMID: 29191629. , 
 #1 Anyway, thank you very much for your comment ,