IL-1β stimulates ADAMTS9 expression and contributes to preterm prelabor rupture of membranes
Abstract 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...
Saved in:
| Main Authors: | , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2025-03-01
|
| Series: | Cell Communication and Signaling |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12964-025-02120-3 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850028150087483392 |
|---|---|
| author | Jiasong Cao Yixin Wang Qimei Lin Shuqi Wang Yongmei Shen Lei Zhang Wen Li Ling Chen Chunliu Liu Shihan Yao Ling Shuai Xu Chen Zongjin Li Ying Chang |
| author_facet | Jiasong Cao Yixin Wang Qimei Lin Shuqi Wang Yongmei Shen Lei Zhang Wen Li Ling Chen Chunliu Liu Shihan Yao Ling Shuai Xu Chen Zongjin Li Ying Chang |
| author_sort | Jiasong Cao |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-a50433d702b84e39bbeaba47f4e93176 |
| institution | DOAJ |
| issn | 1478-811X |
| language | English |
| publishDate | 2025-03-01 |
| publisher | BMC |
| record_format | Article |
| series | Cell Communication and Signaling |
| spelling | doaj-art-a50433d702b84e39bbeaba47f4e931762025-08-20T02:59:54ZengBMCCell Communication and Signaling1478-811X2025-03-0123111810.1186/s12964-025-02120-3IL-1β stimulates ADAMTS9 expression and contributes to preterm prelabor rupture of membranesJiasong Cao0Yixin Wang1Qimei Lin2Shuqi Wang3Yongmei Shen4Lei Zhang5Wen Li6Ling Chen7Chunliu Liu8Shihan Yao9Ling Shuai10Xu Chen11Zongjin Li12Ying Chang13Tianjin Key Laboratory of Human Development and Reproductive Regulation, Tianjin Central Hospital of Gynecology ObstetricsSchool of Medicine, Nankai UniversityTianjin Key Laboratory of Human Development and Reproductive Regulation, Tianjin Central Hospital of Gynecology ObstetricsTianjin Key Laboratory of Human Development and Reproductive Regulation, Tianjin Central Hospital of Gynecology ObstetricsTianjin Key Laboratory of Human Development and Reproductive Regulation, Tianjin Central Hospital of Gynecology ObstetricsTianjin Key Laboratory of Human Development and Reproductive Regulation, Tianjin Central Hospital of Gynecology ObstetricsTianjin Key Laboratory of Human Development and Reproductive Regulation, Tianjin Central Hospital of Gynecology ObstetricsTianjin Key Laboratory of Human Development and Reproductive Regulation, Tianjin Central Hospital of Gynecology ObstetricsTianjin Academy of Traditional Chinese Medicine Affiliated HospitalNankai University Affiliated Hospital of Obstetrics and GynecologyTianjin Key Laboratory of Human Development and Reproductive Regulation, Tianjin Central Hospital of Gynecology ObstetricsTianjin Key Laboratory of Human Development and Reproductive Regulation, Tianjin Central Hospital of Gynecology ObstetricsTianjin Key Laboratory of Human Development and Reproductive Regulation, Tianjin Central Hospital of Gynecology ObstetricsTianjin Key Laboratory of Human Development and Reproductive Regulation, Tianjin Central Hospital of Gynecology ObstetricsAbstract 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.https://doi.org/10.1186/s12964-025-02120-3Preterm prelabor rupture of fetal membranesInterleukin-1 betaADAMTS9NF-kappa BProtein O-fucosyltransferase 2 |
| spellingShingle | Jiasong Cao Yixin Wang Qimei Lin Shuqi Wang Yongmei Shen Lei Zhang Wen Li Ling Chen Chunliu Liu Shihan Yao Ling Shuai Xu Chen Zongjin Li Ying Chang IL-1β stimulates ADAMTS9 expression and contributes to preterm prelabor rupture of membranes Cell Communication and Signaling Preterm prelabor rupture of fetal membranes Interleukin-1 beta ADAMTS9 NF-kappa B Protein O-fucosyltransferase 2 |
| title | IL-1β stimulates ADAMTS9 expression and contributes to preterm prelabor rupture of membranes |
| title_full | IL-1β stimulates ADAMTS9 expression and contributes to preterm prelabor rupture of membranes |
| title_fullStr | IL-1β stimulates ADAMTS9 expression and contributes to preterm prelabor rupture of membranes |
| title_full_unstemmed | IL-1β stimulates ADAMTS9 expression and contributes to preterm prelabor rupture of membranes |
| title_short | IL-1β stimulates ADAMTS9 expression and contributes to preterm prelabor rupture of membranes |
| title_sort | il 1β stimulates adamts9 expression and contributes to preterm prelabor rupture of membranes |
| topic | Preterm prelabor rupture of fetal membranes Interleukin-1 beta ADAMTS9 NF-kappa B Protein O-fucosyltransferase 2 |
| url | https://doi.org/10.1186/s12964-025-02120-3 |
| work_keys_str_mv | AT jiasongcao il1bstimulatesadamts9expressionandcontributestopretermprelaborruptureofmembranes AT yixinwang il1bstimulatesadamts9expressionandcontributestopretermprelaborruptureofmembranes AT qimeilin il1bstimulatesadamts9expressionandcontributestopretermprelaborruptureofmembranes AT shuqiwang il1bstimulatesadamts9expressionandcontributestopretermprelaborruptureofmembranes AT yongmeishen il1bstimulatesadamts9expressionandcontributestopretermprelaborruptureofmembranes AT leizhang il1bstimulatesadamts9expressionandcontributestopretermprelaborruptureofmembranes AT wenli il1bstimulatesadamts9expressionandcontributestopretermprelaborruptureofmembranes AT lingchen il1bstimulatesadamts9expressionandcontributestopretermprelaborruptureofmembranes AT chunliuliu il1bstimulatesadamts9expressionandcontributestopretermprelaborruptureofmembranes AT shihanyao il1bstimulatesadamts9expressionandcontributestopretermprelaborruptureofmembranes AT lingshuai il1bstimulatesadamts9expressionandcontributestopretermprelaborruptureofmembranes AT xuchen il1bstimulatesadamts9expressionandcontributestopretermprelaborruptureofmembranes AT zongjinli il1bstimulatesadamts9expressionandcontributestopretermprelaborruptureofmembranes AT yingchang il1bstimulatesadamts9expressionandcontributestopretermprelaborruptureofmembranes |