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Progesterone Exposure Prevents Matrix Metalloproteinase-3 (MMP-3) Stimulation by Interleukin-1 in Human Endometrial Stromal Cells¹

Department of Cellular and Molecular Pathology and the Women’s Reproductive Health Research Center, Department of Obstetrics and Gynecology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232

Address all correspondence and requests for reprints to: Kevin G. Osteen, Ph.D., Women’s Reproductive Health Research Center, B-1100 Medical Center North, Vanderbilt University School of Medicine, Nashville, Tennessee 37232. E-mail: kevin.osteen{at}mcmail.vanderbilt.edu

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 (IL-1), can oppose progesterone suppression of MMPs in the human endometrium. Furthermore, we have recently demonstrated colocalization of epithelial cell IL-1 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 in regulation of MMP-3. Although IL-1 is a potent stimulator of MMP-3 in proliferative phase endometrium in organ culture, we demonstrate that progesterone exposure in vivo reduces IL-1 stimulation of MMP-3 in secretory phase tissue. This loss of sensitivity to IL-1 was duplicated in isolated stromal cells treated with progesterone in vitro, and IL-1 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. 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.

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