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Production of Interleukin-1 by Human Endometrial Stromal Cells Is Triggered during Menses and Dysfunctional Bleeding and Is Induced in Culture by Epithelial Interleukin-1 Released upon Ovarian Steroids Withdrawal

Cell Biology Unit (C.M.P., H.P.G.C., P.B.C., D.D., P.J.C., E.M., P.H.), de Duve Institute, and Department of Pathology (P.B.C., C.G., D.D., E.M.), Université catholique de Louvain, B-1200 Bruxelles, Belgium

Address all correspondence and requests for reprints to: Patrick Henriet, CELL Unit, de Duve Institute, UCL-75.41, 75 avenue Hippocrate, B-1200 Bruxelles, Belgium. E-mail: patrick.henriet{at}uclouvain.be.

Context: Endometrial breakdown during menstruation and dysfunctional bleeding is triggered by the abrupt expression of matrix metalloproteinases (MMPs), including interstitial collagenase (MMP-1). The paracrine induction of MMP-1 in stromal cells via epithelium-derived IL-1 is repressed by ovarian steroids. However, the control by estradiol (E) and progesterone (P) of endometrial IL-1 expression and bioactivity remains unknown.

Objective and Design: Variations of endometrial IL-1 mRNA and protein along the menstrual cycle and during dysfunctional bleeding were determined using RT-PCR, in situ hybridization, and immunolabeling. The mechanism of EP control was analyzed using culture of explants, laser capture microdissection, and purified cells. Data were compared with expression changes of IL-1β and IL-1 receptor antagonist.

Results: IL-1 is synthesized by epithelial cells throughout the cycle but E and/or P prevents its release. In contrast, endometrial stromal cells produce IL-1 only at menses and during irregular bleeding in areas of tissue breakdown. Stromal expression of IL-1, like that of MMP-1, is repressed by P (alone or with E) but triggered by epithelium-derived IL-1 released upon EP withdrawal.

Conclusions: Our experiments in cultured endometrium suggest that IL-1 released by epithelial cells triggers the production of IL-1 by stromal cells in a paracrine amplification loop to induce MMP-1 expression during menstruation and dysfunctional bleeding. All three steps of this amplification cascade are repressed by EP.