Interaction of macrophages and endometrial cells induces epithelial-mesenchymal transition-like processes in adenomyosis

Abstract

Adenomyosis is a nonneoplastic condition characterized by the benign invasion of ectopic endometrium into the myometrium. Macrophages play significant roles in epithelial-mesenchymal transition (EMT) and adenomyosis. An EMT associated with adenomyosis has been extensively studied. This study investigated the process by which the interaction of macrophages with endometrial cells induces EMT in Ishikawa cells and epithelial cells of adenomyosis. Specimens were collected after hysterectomy or resection of adenomyosis lesions from women with adenomyosis and curettage from women without adenomyosis or endometriosis. Immunohistochemistry and immunofluorescent staining demonstrated that CD68-positive macrophages aggregated in adenomyosis lesions, along with the increased protein expressions of n-cadherin, vimentin, and S100A4. By contrast, the protein expressions of e-cadherin and CK7 were decreased. After the primary endometrium cells were cocultured with THP-1-derived macrophages, the protein expression levels of n-cadherin, vimentin, and S100A4 of endometrium cells were increased, whereas the protein expression levels of e-cadherin and CK7 were decreased. The proportion of alternatively activated (M2) macrophages derived from THP-1 macrophages was also increased. The M2 macrophages elicited a bidirectional effect on Ishikawa cells by inducing EMT-like or mesenchymal-epithelial transition-like processes. The apoptotic rate of the Ishikawa cells cocultured with macrophages was increased, whereas their cell proliferation rate was decreased. Transmission electron microscopy indicated that the number of intercellular junctions of the cocultured Ishikawa cells was reduced. Microarray-based gene expression analysis revealed that transforming growth factor-β1/Smad3 and interleukin-6/JAK2/STAT3 signaling pathways were upregulated. Therefore, macrophages can induce EMT-like processes in adenomyosis and undergo polarization to M2.

Keywords: Ishikawa; adenomyosis; epithelial–mesenchymal transition; macrophages.