Paracrine stimulation of interstitial collagenase (MMP-1) in the human endometrium by interleukin 1 alpha and its dual block by ovarian steroids

In the cycling human endometrium, the expression of interstitial collagenase (MMP-1) and of several related matrix metalloproteinases (MMPs) follows the late-secretory fall in sex steroid plasma concentrations and is thought to be a critical step leading to menstruation, The rapid and extensive lysis of interstitial matrix that precedes menstrual shedding requires a strict control of these proteinases, However, the mechanism by which ovarian steroids regulate endometrial MMPs remains unclear, We report here that, in the absence of ovarian steroids, MMP-1 expression in endometrial fibroblasts is markedly stimulated by medium conditioned by endometrial epithelial cells, This stimulation can be prevented by antibodies directed against interleukin 1 alpha (IL-1 alpha) but not against several other cytokines. Ovarian steroids inhibit the release of IL-1 alpha and repress MMP-1 production by IL-1 alpha-stimulated fibroblasts. In short-term cultures of endometrial explants obtained throughout the menstrual cycle, the release of both IL-1 alpha and MMP-1 is essentially limited to the perimenstrual phase, We conclude that epithelium-derived IL-1 alpha is the key paracrine inducer of MMP-1 in endometrial fibroblasts. However, MMP-1 production in the human endometrium is ultimately blocked by ovarian steroids, which act both upstream and downstream of IL-1 alpha, thereby exerting an effective control via a ''double-block'' mechanism.