Maternal Glucocorticoids Make the Fetal Membrane Thinner: Involvement of Amniotic Macrophages

Glucocorticoid use during pregnancy is known to increase the risk of preterm birth and preterm premature rupture of membranes (pPROM). Here, we investigated the mechanism of how glucocorticoids weaken the fetal membranes. The amnion mesenchymal layer was significantly thinner in pregnant women treated with prednisolone and in corticosterone-injected mice than in control groups. Matrix metalloproteinase (MMP)-9 mRNA and its activity, COX2 mRNA levels, and prostaglandin E2 synthesis were increased, whereas type 1 collagen (COL1A1) mRNA levels were decreased in the fetal membranes of corticosterone-injected mice. Unexpectedly, the proliferation and migration of macrophages were observed around the corticosterone-injected amnion, and IL-1β was released from these macrophages. In human amnion mesenchymal cells, cortisol did not change MMP mRNA expression, whereas IL-1β treatment robustly increased MMP and COX2 mRNA expression. COL1A1 mRNA level was decreased by both cortisol and IL-1β. These data suggest that the recruitment of amniotic macrophages by glucocorticoids plays a pivotal role in weakening of the fetal membranes, leading to the pathogenesis of pPROM.