Cytokines and human endometrial function: Abnormalities in recurrent miscarriage women.

The human endometrium is the site of embryo implantation and is therefore responsible for providing a suitable environment for an embryo to grow and develop. This is achieved by the endometrium undergoing cyclical changes, under the control of steroid hormones. However, it is clear that steroid hormones are not the final effectors, but rather initiate a downstream cascade of molecular events through local autocrine and paracrine factors, such as cytokines. The role of cytokines in the human endometrium still remains to be determined, but they are thought to play an important role in the implantation process. This study has therefore focused on the expression of pro-inflammatory cytokines in the human endometrium and effects of these cytokines on endometrial function. Immunocytochemistry was used to determine the expression of leukaemia inhibitory factor (LIF), interleukin-6 (IL-6), interleukin-1alpha (IL-1alpha), interleukin-1beta (IL-1beta) and tumour necrosis factor alpha (TNFalpha) in the human endometrium of normal fertile women throughout the menstrual cycle. The results showed that staining intensity for LIF and IL-6 increased in epithelial cells at the time of implantation. IL-1alpha and IL-1beta remained relatively constant throughout the cycle, with a slight increase in epithelial IL-1B at the time of implantation. The expression of TNFalpha could not be determined. Staining for LIF, IL-6, IL-1alpha and IL-1beta was then repeated on endometrial sections from biopsies obtained from women who suffer recurrent miscarriage at the time of implantation and compared to the staining obtained in biopsies from normal fertile women. For all four cytokines, there were some biopsies from women who suffer recurrent miscarriage, where staining was significantly weaker than that seen in normal fertile women at the same time in the menstrual cycle. These results suggest that LIF, IL-6, IL-1alpha and IL-1beta may therefore be important for successful implantation and subsequently successful pregnancy outcome.Matrix metalloproteinases (MMPs) are postulated to be involved in the implantation process, as they are capable of digesting the components of the extracellular matrix. Recent studies have shown that cytokines may be involved in the regulation of MMPs in both the endometrium and the invading trophoblast cells. The effects of LIF, IL-6, IL-1beta and TNFalpha on endometrial MMP production in vitro were thereforeinvestigated. MMP-2 was produced by both cultured epithelial and stromal cells, MMP-9 was produced mainly by epithelial cells and MMP-7 was only produced by epithelial cells. Although LIF and IL-6 had no significant effect on endometrial MMP production, IL-1alpha and TNFalpha did alter MMP-2, MMP-9 and MMP-7 production from both epithelial and stromal cells.More recent studies have suggested the possible role of interleukin-11 (IL-11) in endometrial function, particularly decidualisation. Therefore the expression of both IL-11 and its receptor, IL-11R, was investigated in endometrial biopsies obtained from normal fertile women throughout the menstrual cycle. The results showed that both IL-11 and IL-11R were expressed throughout the menstrual cycle, predominantly by epithelial cells, however, stromal expression did increase slightly towards the end of the cycle. The effects of cytokines on IL-11 production by cultured endometrial cells were also investigated. IL-1alpha, TNFalpha and TGFbeta caused a significant increase in IL-11 production from both stromal and epithelial cells. Finally the effects of IL-11 on MMP-2, MMP-9, MMP-7, IL-1beta and TNFalpha produced by cultured endometrial cells were studied. No effect of IL-11 on MMP production was seen by either stromal or epithelial cells, but IL-11 did cause a concentration dependent decrease in TNFalpha production from cultured epithelial cells.The results have increased our knowledge on the expression and function of endometrial pro-inflammatory cytokines and suggested that although endometrial LIF and IL-6 expression is greatest at the time of implantation and is decreased in women who suffer recurrent miscarriage, IL-1 and TNFalpha have a greater effect on endometrial function. IL-11 is also expressed by the endometrium and is affected by other cytokines. Its positioning within the cytokine networks, which could control endometrial function, requires further study.