Preterm premature
rupture of membranes (pPROMs) account for one-third of
preterm births, a leading cause of
neonatal death. Understanding the mechanism of membrane
rupture is thus of clinical significance in the prevention of
preterm birth. Parturition at both term and preterm is associated with increased abundance of proinflammatory
cytokines in the fetal membranes regardless of the presence of
infection, which is believed to induce
rupture of membranes through activation of the
matrix metalloproteinases. It remains unknown whether there are any alternative mechanisms underpinning proinflammatory
cytokine-induced
rupture of membranes. Here we showed that there were reciprocal increases in interleukin-1β (IL-1β) and decreases in
lysyl oxidase (LOX), a
collagen crosslinking
enzyme, in the human amnion tissue following
spontaneous rupture of membrane at term and
pPROM. Studies using human amnion tissue explants revealed that IL-1β inhibited the expression of LOX, which can be reproduced in cultured human amnion fibroblasts. Mechanistic study revealed that IL-1β inhibited LOX expression through activation of p38 and Erk1/2
mitogen-activated protein kinase pathways, which resulted in the phosphorylation of the nuclear factor kappa light-chain enhancer of activated B (NF-κB) cell subunit p65 as well as GATA
binding protein 3 (GATA3). Subsequently, activated NF-κB interacted with GATA3 at the NF-κB binding site of LOX promoter to inhibit its expression. Conclusively, this study has revealed an alternative mechanism that IL-1β may contribute to the
rupture of membranes by attenuating
collagen crosslinking through downregulation of LOX expression in amnion fibroblasts.