Multiplicité des niveaux de contrôle de la bioactivité de l'interleukin-1alpha par les stéroïdes ovariens dans l'endomètre humain

Extracellular matrix remodelling is under tight regulation. In particular, cyclical\nmodifications in the human endometrium are globally controlled by the fluctuations in the\nconcentrations of the ovarian steroids, oestrogen and progesterone. The elimination of the\nsuperficial layer of the human endometrium is normally restricted to menstruation, in\nresponse to the sudden fall in the concentration of these hormones at the end of the cycle, but\nit also occurs during irregular bleeding episodes. During these physiopathological events of\nendometrial degradation, the activity of matrix metalloproteinases (MMPs), among which\ncollagenases, remains finely regulated in time and space due to the action of a network of\ncytokines, mainly interleukin-1a (IL-1a). Former studies from the laboratory had identified in\nvitro a paracrine mechanism of induction of collagenase-1 (MMP-1) production by stromal\nfibroblasts in response to IL-1a released from epithelial cells. The aims of my work were to\nnarrow down the mechanisms controlling the expression and bioactivity of IL-1a in the\nendometrium in vivo, in particular in the context of menstrual or pathological induction of\ncollagenase.\nVariations in the mRNA and protein concentrations of IL-1a were measured by\nquantitative RT-PCR and ELISA in endometrial samples collected during the different phases\nof the cycle or during irregular bleeding episodes. IL-1a mRNA and protein were also\nlocalized by in situ hybridization and immunohistochemistry in order to specify their cellular\norigin using antibodies specific to cell type markers. The effect of ovarian steroids on the\ncontrol of IL-1a expression and release was directly investigated in culture of explants and\npurified cells.\nA major difference in the action of ovarian steroids on IL-1a was evidenced between\nglands and stroma. Epithelial cells synthesize IL-1a throughout the menstrual cycle but do not\nrelease it except in response to the fall in the concentration of both oestradiol and\nprogesterone. Once released, epithelial-derived IL-1a induces its own paracrine amplification\nby stromal fibroblasts. However, this amplification is inhibited by the ovarian steroids which\ntherefore exert a double blocking action : by preventing epithelial release and fibroblastic\nsynthesis of IL-1a. As a consequence, the production of IL-1a by the endometrial stroma is\nstrictly restricted to menstruation and irregular bleeding episodes. Released IL-1a induces the\nfibroblastic production of MMP-1 but is not responsible for that of MMP-8, although my\ninvestigations by in situ hybridization and immunolabelling clearly show a parallelism in\nexpression and hormonal repression of both these metalloproteinases.\nIn summary, my data show that IL-1a is expressed by at least two different types of\nresident cells in the human endometrium and point to the multiplicity in the levels of\nhormonal control on this cytokine. They offer a substantial support to the major contribution\nof IL-1a to trigger and locally control physiopathological tissue breakdown.