The nuclear factor-κB pathway is involved in matrix metalloproteinase-9 expression in RU486-induced endometrium breakdown in mice
Authors: Li, Yun-Feng; Xu, Xiang-Bo; Chen, Xi-Hua; Wei, Gang; He, Bin; Wang, Jie-Dong
Source: Human Reproduction, Volume 27, Number 7, 6 July 2012 , pp. 2096-2106(11)
Publisher: Oxford University Press
Abstract:BACKGROUNDProgesterone-withdrawal (WP)-induced endometrial breakdown occurs in both physiological and pathological processes such as menstruation and abortion. However, the underlying mechanisms are not clearly understood. As the nuclear factor-κB (NF-κB) pathway has been proposed to play a role in endometrial breakdown, we tested this hypothesis using RU486-induced mouse menstruation-like model.METHODSThe activation of NF-κB was evaluated by immunohistochemistry, western blot and immunofluorescence. The expression of matrix metalloproteinase-9 (MMP9) was analyzed by real-time PCR and its proteins by gelatin zymography and western blot. Chromatin immunoprecipitation was used to investigate the direct binding of NF-κB to MMP9 gene promoter. Inhibitors of NF-κB were used to block its signal in vivo and in vitro to analyze the function of NF-κB in the tissue breakdown process.RESULTSAdministration of RU486 resulted in increased phospho-IκB levels and nuclear translocation of p65 in decidual stromal cells, accompanied by the up-regulation of NF-κB inducing kinase and IκB kinase β mRNA. The NF-κB inhibitor, `pyrrolidine dithiocarbamate' partially suppressed the RU486-induced endometrial breakdown, thus verifying the role of this pathway in vivo. MMP9 was up- and down-regulated following the NF-κB activation and inhibition, respectively. RU486 stimulated recruitment of NF-κB p65 to the MMP9 promoter and further increased its expression. Effects of NF-κB activation and inactivation on MMP9 expression were further explored in human stromal cells in vitro. A similar MMP9 expression pattern was observed in cultured human, as well as mouse, decidual stromal cells following RU486 treatment.CONCLUSIONSThe activation of the NF-κB pathway induces downstream target genes, including MMP9 from stromal cells to facilitate tissue breakdown in mouse uterus, highlighting the likelihood that this regulatory pattern exists in the human endometrium.
Document Type: Research article
Publication date: 2012-07-06
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