Regulation of hepatocyte growth factor by basal and stimulated macrophages in women with endometriosis
1 Department of Obstetrics and Gynecology, 2 Division of Cytokine Signaling, Department of Molecular Microbiology and Immunology, Graduate School of Biomedical Sciences and 3 Department of Molecular Pathology, Atomic Bomb Disease Institute, Nagasaki University, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan
4 To whom correspondence should be addressed. Email: nemokhan{at}net.nagasaki-u.ac.jp
BACKGROUND: The different macromolecules as secreted by macrophages (M
) in the pelvic environment are believed to enhance the growth of endometriosis. However, the possible mediator that stimulates M for the production of different growth factors is not well described. Therefore, we investigated the possible production of hepatocyte growth factor (HGF) by the basal and lipopolysaccharide (LPS)-stimulated M derived from women with or without endometriosis. METHODS: Using primary culture and 4-well chamber slides, adherent M immunoreactive to CD68 were isolated from the peritoneal fluid (PF) of 20 infertile women with endometriosis and 12 women without endometriosis. The proliferation of basal and LPS-treated M was investigated by the dimethylthiazole tetrazolioum bromide (MTT) assay. The production of HGF in the culture media of basal and LPS-stimulated M was examined by enyme-linked immunosorbent assay. The expression of mRNA for HGF and its receptor, c-Met, in the M was investigated by RT–PCR. The effect of HGF on the growth of endometrial cells and M was analysed by bromodeoxyuridine (BrdU) incorporation. RESULTS: A >100% increase in the proliferation of peritoneal M derived from women with endometriosis, and particularly of those harbouring dominant red lesions, was observed after treatment with LPS (P<0.05). A 4- and 3-fold increase in the production of HGF was observed by the LPS-treated M derived from women with stage I–II endometriosis and stage III–IV endometriosis, respectively, when compared with non-LPS-treated M (P<0.001). At the transcriptional level, we found a 5-fold increase in HGF mRNA expression in LPS-treated M versus basal M in women with endometriosis (P<0.001). The BrdU incorporation study indicates that 10–100 ng/ml of HGF enhanced the growth of endometrial epithelial cells, stroma and M (
50% increase) derived from women with endometriosis (all P<0.05). CONCLUSION: LPS could be an inflammatory mediator of macrophage stimulation in the pelvic microenvironment. Besides mesenchymal cells, HGF is also produced by peritoneal M and is possibly involved in the growth of endometriosis.
Key words: cell growth/endometriosis/hepatocyte growth factor/lipopolysaccharide/macrophage
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