To clarify the role of macrophages and macrophage colony-stimulating factor (M-CSF) in follicular development and ovulation, the processes of folliculogenesis and ovulation, numerical changes in macrophages, and proliferative capacity of granulosa cells were examined in op/op mice before or after daily M-CSF administration. The natural estrous cycle was determined daily by means of vaginal smears. The number of ovulated ova in both fallopian tubes was significantly smaller in op/op mice than in normal littermates. Such ova markedly increased in number after daily M-CSF administration. The numbers of both antral and mature follicles in the proestrous ovary were markedly lower in op/op mice than in the controls and increased after daily M-CSF administration. Flash-labeling with [3H]thymidine showed that the proliferative capacity of granulosa cells in antral follicles was reduced in op/op mice but elevated after daily M-CSF administration. Numbers of granulosa cells and macrophages in the antral follicles were significantly decreased in op/op mice but were increased after M-CSF treatment. All these data provide evidence that macrophages are implicated in the process of folliculogenesis and ovulation.
In human chorionic villi, numerous macrophages, so-called Hofbauer cells, are located adjacent to trophoblasts. To determine the role of the macrophages in the proliferation and differentiation of trophoblasts, cytotrophoblast cells were cultured in serum-free culture-conditioned media of villous macrophages (VMCM), peritoneal macrophages (PMCM), and villous fibroblasts (VFCM). In VMCM, proliferation of cytotrophoblast cells was detected at 24 h by immunocytochemistry with Ki-67-antibody. A large number (P < 0.001) of multinucleated syncytia was formed in VMCM. In VMCM, cytotrophoblast cell fusion was completed by 96 h, which coincided with the peak of hCG secretion and initiation of human placental lactogen (hPL) release. Levels of hCG (P < 0.001) and hPL (P < 0. 001) secretion from syncytial cells were significantly higher in VMCM than in PMCM or in VFCM. Concentrations of macrophage colony-stimulating factor (M-CSF) and vascular endothelial growth factor (VEGF) analyzed by ELISA were greater in VMCM than in PMCM or in VFCM, whereas monocyte chemoattractant protein-1 (MCP-1) concentration was high in PMCM. The expression patterns of M-CSF, VEGF, and MCP-1 in villous macrophages and peritoneal macrophages by reverse transcriptase-polymerase chain reaction were similar to their secretion patterns. Thus, villous macrophages have a greater ability to stimulate hCG and hPL secretion than do peritoneal macrophages. This study suggests that macrophages within the villous stroma may stimulate the growth and differentiation of trophoblasts through their secreted substances.
The effects of macrophages on granulosa cell proliferation were examined using gonadotropin-primed immature female rats and osteopetrotic (op/op) mice, a model defective in monocyte-macrophage lineage cells. Macrophages were found in the follicles at various developmental stages in rats and mice. The labeling index with [3H]thymidine of cultured rat granulosa cells was maximal when they were cultured with peritoneal macrophages at a macrophages:granulosa cell ratio of 0.01. This ratio was similar to those in rat preantral and antral follicles in vivo. In op/op mice, the number of developing follicles was markedly reduced, but increased after daily macrophage-colony-stimulating factor (M-CSF) administration. In the antral follicles of op/op mice, both granulosa cells and macrophages were significantly decreased in number but were increased after M-CSF treatment. Double immunohistochemical staining revealed that epidermal growth factor (EGF)-positive cells were macrophages in the developing rat follicles. These findings suggest that macrophages are located in the developing follicles and participate in promoting granulosa cell growth through a paracrine mechanism by secreting EGF and other cytokines.
It is well known that the number of peritoneal macrophages is increased in patients with pelvic endometriosis. We measured the concentration of monocyte chemoattractant protein-1 (MCP-1) using an enzyme-linked immunosorbent assay (ELISA) in the peritoneal fluid of women with and without endometriosis. The expression of MCP-1 in pelvic endometriotic lesions obtained from the peritoneum was also examined using immunohistochemistry and nonradioactive in situ hybridization. The mean concentration of MCP-1 in the peritoneal fluid was significantly higher in the patients with endometriosis (P<0.05). The most significant elevation, compared with non-endometriosis patients, was found in stage I of the disease (P<0.05). However, no statistically significant difference was found among endometriosis stages I, II, III, and IV. Immunohistochemical staining revealed that MCP-1-positive cells were localized in the glandular epithelium of the endometriotic lesions and in the stromal macrophages distributed in those lesions, but normal peritoneal cells were negative. The in situ hybridization method demonstrated expression of MCP-1 mRNA on the endometriotic glandular epithelium and stromal macrophages. These findings suggest that MCP-1 may be involved in the histogenesis and early development of peritoneal endometriosis.
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