Journal Article

IL-1β stimulates ADAMTS9 expression and contributes to preterm prelabor rupture of membranes

Lin, Qimei, Wang, Yixin, Zhang, Lei, Li, Wen, Shuai, Ling, Chen, Xu, Liu, Chunliu, Yao, Shihan, Li, Zongjin, Chang, Ying, Shen, Yongmei, Wang, Shuqi, Chen, Ling, Cao, Jiasong

2025

Overview

Background Preterm prelabor rupture of membranes (pPROM) is a leading cause of neonatal morbidity and mortality. While intra-amniotic infection is a well-established driver of pPROM, the role of sterile intra-amniotic inflammation remains unclear. Recent evidence suggests that interleukin-1 beta (IL-1β) promotes extracellular matrix (ECM) remodeling via downstream effectors, a disintegrin-like and metalloproteinase domain with thrombospondin type 1 motif 9 (ADAMTS9), while protein O-fucosyltransferase 2 (POFUT2) facilitates its O-fucosylation and secretion, amplifying ECM degradation. This study investigates how IL-1β-triggered nuclear factor kappa-B (NF-κB) activation promotes ADAMTS9 and POFUT2 expression, ultimately driving fetal membrane ECM remodeling and weakening in pPROM without signs of intra-amniotic infection. Methods A nested case-control study included maternal serum and fetal membrane samples from 60 pregnant women (34 pPROM, 26 full-term births [FTB]). ELISA measured serum levels of IL-1β and ADAMTS9, and their correlations were analyzed. Mechanistic studies utilized primary human amniotic epithelial cells (hAECs) and fetal membrane-decidua explants with IL-1β treatment. The role of NF-κB was explored using chromatin immunoprecipitation (ChIP) and luciferase assays to assess NF-κB binding to the promoters of ADAMTS9 and POFUT2. A murine model of sterile intra-amniotic inflammation under ultrasound-guided IL-1β injection was used to validate in vitro findings and assess pregnancy outcomes. Results Serum IL-1β and ADAMTS9 levels at 16 weeks of gestation were significantly higher in pPROM cases compared to FTB controls ( P  < 0.001). A combined model of these biomarkers demonstrated high predictive accuracy for pPROM (AUC = 0.83). Mechanistically, IL-1β activated NF-κB, leading to its binding to the promoters of ADAMTS9 and POFUT2. NF-κB activation promoted ADAMTS9 expression, while POFUT2 enhanced its secretion. Together, these processes drove versican degradation and ECM weakening. Intra-amniotic administration of IL-1β in mice induced fetal membrane weakening, preterm birth, and adverse neonatal outcomes, which were mitigated by the NF-κB inhibitor BAY 11-7082 treatment. Conclusion Maternal serum ADAMTS9 levels at mid-gestation are promising non-invasive biomarkers for pPROM risk stratification. Mechanistically, IL-1β-induced NF-κB activation promotes ADAMTS9 expression and POFUT2-dependent secretion, contributing to fetal membrane weakening. These findings provide new insights into the role and potential therapeutic target for sterile intra-amniotic inflammation in pPROM.

• Publisher: BioMed Central,Springer Nature B.V,BMC
• Subject: ADAMTS9 / ADAMTS9 Protein - blood / ADAMTS9 Protein - genetics / ADAMTS9 Protein - metabolism / Adult / Animal models / Animals / Antibiotics / Biomarkers / Biomedical and Life Sciences / Case-Control Studies / Cell Biology / Cesarean section / Chromatin / Cytokines / Cytokines and Growth Factors / Decidua / Enzyme-linked immunosorbent assay / Epithelial cells / Explants / Extracellular matrix / Female / Fetal Membranes, Premature Rupture - blood / Fetal Membranes, Premature Rupture - genetics / Fetal Membranes, Premature Rupture - metabolism / Fetal Membranes, Premature Rupture - pathology / Galactoside 2-a-L-fucosyltransferase / Gestation / Gestational age / Heart rate / Humans / IL-1β / Immunoprecipitation / Infections / Inflammation / Interleukin 1 / Interleukin-1 beta / Interleukin-1beta - blood / Interleukin-1beta - metabolism / Kinases / Life Sciences / Membranes / Mice / Morbidity / Neonates / NF-kappa B / NF-kappa B - metabolism / NF-κB protein / Pregnancy / Pregnancy complications / Premature birth / Preterm prelabor rupture of fetal membranes / Promoters / Protein O-fucosyltransferase 2 / Protein-Ligand Interactions / Receptors / Serum levels / Therapeutic targets / Thrombospondin / Tumor necrosis factor-TNF / Ultrasonic imaging / Versican