Multiplicité des niveaux de contrôle de la bioactivité de l'interleukin-1alpha par les stéroïdes ovariens dans l'endomètre humain
(2009)
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- (en) Extracellular matrix remodelling is under tight regulation. In particular, cyclical modifications in the human endometrium are globally controlled by the fluctuations in the concentrations of the ovarian steroids, oestrogen and progesterone. The elimination of the superficial layer of the human endometrium is normally restricted to menstruation, in response to the sudden fall in the concentration of these hormones at the end of the cycle, but it also occurs during irregular bleeding episodes. During these physiopathological events of endometrial degradation, the activity of matrix metalloproteinases (MMPs), among which collagenases, remains finely regulated in time and space due to the action of a network of cytokines, mainly interleukin-1a (IL-1a). Former studies from the laboratory had identified in vitro a paracrine mechanism of induction of collagenase-1 (MMP-1) production by stromal fibroblasts in response to IL-1a released from epithelial cells. The aims of my work were to narrow down the mechanisms controlling the expression and bioactivity of IL-1a in the endometrium in vivo, in particular in the context of menstrual or pathological induction of collagenase. Variations in the mRNA and protein concentrations of IL-1a were measured by quantitative RT-PCR and ELISA in endometrial samples collected during the different phases of the cycle or during irregular bleeding episodes. IL-1a mRNA and protein were also localized by in situ hybridization and immunohistochemistry in order to specify their cellular origin using antibodies specific to cell type markers. The effect of ovarian steroids on the control of IL-1a expression and release was directly investigated in culture of explants and purified cells. A major difference in the action of ovarian steroids on IL-1a was evidenced between glands and stroma. Epithelial cells synthesize IL-1a throughout the menstrual cycle but do not release it except in response to the fall in the concentration of both oestradiol and progesterone. Once released, epithelial-derived IL-1a induces its own paracrine amplification by stromal fibroblasts. However, this amplification is inhibited by the ovarian steroids which therefore exert a double blocking action : by preventing epithelial release and fibroblastic synthesis of IL-1a. As a consequence, the production of IL-1a by the endometrial stroma is strictly restricted to menstruation and irregular bleeding episodes. Released IL-1a induces the fibroblastic production of MMP-1 but is not responsible for that of MMP-8, although my investigations by in situ hybridization and immunolabelling clearly show a parallelism in expression and hormonal repression of both these metalloproteinases. In summary, my data show that IL-1a is expressed by at least two different types of resident cells in the human endometrium and point to the multiplicity in the levels of hormonal control on this cytokine. They offer a substantial support to the major contribution of IL-1a to trigger and locally control physiopathological tissue breakdown.
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Pretto, C. (2009). Multiplicité des niveaux de contrôle de la bioactivité de l’interleukin-1alpha par les stéroïdes ovariens dans l’endomètre humain. https://hdl.handle.net/2078.5/131388