Upregulation of TNF-α and IL-6 induces preterm premature rupture of membranes by activation of ADAMTS-9 in embryonic membrane cells.

ABSTRACT

AIM: To investigate the role of thrombospondin motifs 9 (ADAMTS9) in preterm premature rupture of membranes (pPROM). MATERIALS AND METHODS: ADAMTS9 levels were measured in amnion cells from 24 patients of different groups (preterm vs. full-term birth, with vs. without PROM). ADAMTS9 was suppressed in human amnioblasts to investigate its effects on embryonic membrane cells and inflammation-induced cell damage. Pregnant mouse models were used to assess whether inflammation regulates ADAMTS9 by upregulating TNF-α and IL-6, contributing to the preterm birth occurrence. KEY FINDINGS: We found that ADAMTS9 protein and gene expression levels significantly differed among various groups (pPROM > full-term PROM > preterm non-PROM > full-term non-PROM). After ADAMTS9 suppression in human amnioblast WISH cells, TNF-α- and IL-6-induced apoptosis was decreased. In addition, TNF-α, IL-6, and ADAMTS9 protein and gene expression levels were increased in the embryos of mice treated with LPS compared with controls. In agreement, the rate of preterm birth was higher in the LPS group compared with controls. SIGNIFICANCE: Taken together, these in vitro and in vivo findings suggest that TNF-α and IL-6 secreted by macrophages during inflammation regulate ADAMTS9 and induce pPROM.