Progesterone exposure prevents matrix metalloproteinase-3 (MMP-3) stimulation by interleukin-1α in human endometrial stromal cells

Suppression of endometrial matrix metalloproteinases (MMPs) is necessary to maintain tissue stability during the invasive events of implantation and placental development. Several laboratories have shown that inflammatory cytokines, including interleukin-1 alpha (IL-1 alpha), can oppose progesterone suppression of MMPs in the human endometrium. Furthermore, we have recently demonstrated colocalization of epithelial cell IL-1 alpha and MMP-7 expression at sites of ectopic pregnancy. The current study extends these findings, revealing a previously unrecognized interrelationship between progesterone and IL-1 alpha in regulation of MMP-S. Although IL-1 alpha is a potent stimulator of MMP-3 in proliferative phase endometrium in organ culture, we demonstrate that progesterone exposure in vivo reduces IL-1 alpha stimulation of MMP-3 in secretory phase tissue. This loss of sensitivity to IL-1 alpha was duplicated in isolated stromal cells treated with progesterone in vitro, and IL-1 alpha stimulation of MMP-3 returned in a dose-dependent manner with progesterone withdrawal. The antiprogestin, onapristone, partially blocked the ability of progesterone to prevent stimulation of MMP-3 by IL-1 alpha. These data suggest a novel mechanism by which progesterone may preserve tissue integrity during the establishment and maintenance of pregnancy by limiting stimulation of MMPs by inflammatory cytokines such as IL-1 alpha.