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 colla genase (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 rapi d and extensive lysis of interstitial matrix that precedes menstrual s hedding requires a strict control of these proteinases, However, the m echanism by which ovarian steroids regulate endometrial MMPs remains u nclear, We report here that, in the absence of ovarian steroids, MMP-1 expression in endometrial fibroblasts is markedly stimulated by mediu m conditioned by endometrial epithelial cells, This stimulation can be prevented by antibodies directed against interleukin 1 alpha (IL-1 al pha) 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 alp ha and MMP-1 is essentially limited to the perimenstrual phase, We con clude 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 effec tive control via a ''double-block'' mechanism.