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)

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Abstract:

BACKGROUND

Progesterone-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.

METHODS

The 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.

RESULTS

Administration 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.

CONCLUSIONS

The 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.

Keywords: NF-κB; MMP9; progesterone withdrawal; tissue breakdown; mifepristone

Document Type: Research article

DOI: http://dx.doi.org/10.1093/humrep/des110

Publication date: 2012-07-06

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Human Reproduction features full-length, peer-reviewed papers reporting original research, clinical case histories, as well as opinions and debates on topical issues. Papers published cover the scientific and medical aspects of reproductive physiology and pathology, endocrinology, andrology, gonad function, gametogenesis, fertilization, embryo development, implantation, pregnancy, genetics, genetic diagnosis, oncology, infectious disease, surgery, contraception, infertility treatment, psychology, ethics and social issues. The highest scientific and editorial standard is maintained throughout the journal along with a rapid rate of publication.

The nuclear factor-κB pathway is involved in matrix metalloproteinase-9 expression in RU486-induced endometrium breakdown in mice

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