2) 顆粒膜細胞における細胞内信号伝達系分子の活性化機序と排卵誘発への応用(シンポジウム1(生殖) 卵巣のダイナミックな変化の神秘に迫る-臨床へのフィードバックを目指して-,第67回日本産科婦人科学会学術講演会講演要旨)

河野,康志

The function of granulosa cells is regulated by various hormones and growth factors. Ovulation shares many features in common with inflammatory reactions, including the participation of leukocytes and classical inflammatory mediators. It has been demonstrated that neutrophilic granulocytes and macrophages are present in the theca layer of follicles during ovulation in humans. In this study, we examined the measurement of chemokine which can recruit the many kinds of leukocyte, and possible role of ovarian function and angiogenic factor in follicular fluid (FF). The concentrations of interleukin (IL)-8 and growth-regulated oncogene (GRO) α, monocyte chemoattractant protein (MCP)-1 and macrophage inflammatory protein (MIP)-3α in FF were significantly higher than those in serum. The regulation of these chemokines were up-regulated by IL-1, epidermal growth factor (EGF), transforming growth factor (TGF)-α and platelet-activating factor (PAF) in cultured human immortalized granulosa cell line (GC1a or KGN). These chemokines were also produced by the activation of protease-activated receptor (PAR)-1. IL-1 act via IkB/NF-kB as the nuclear translocation of NF-kB were detected after IL-1 stimulation by fluorescent staining. EGF, TGFα, PAF and PAR-1 activated the mitogen-activated protein (MAP) kinase, especially extracellular signal-regulated kinase (ERK). These results suggested that chemokines may play an important role in human preovulatory processes involving leukocyte recruitment. We also investigated the angiogenic factor in FF. Vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF) and angiogenin mRNA expression aspirated follicular cells were detected by RT-PCR. The concentrations of VEGF, HGF, and angiogenin in FF were significantly higher than those in serum. VEGF was moderately detected in granulosa cell layer and CD 31 was strongly detected in endothelial cells arround the follicle in normal ovarian tissues by im munohistochemistry. The ERK activity was increased by treatment with HB-EGF or amphiregulin, which bind to EGF receptor. VEGF production was significantly increased by HB-EGF or amphiregulin alone, while it was decreased by EGF receptor tyrosine kinase inhibitoer or MEK inhibitor. Moreover, the effect of low level laser therapy (LLLT) was investigated. ERK activity was increased by LLLT (60mW, GaAlAs 830nm) and it was enhanced by follicle-stimulating hormone (FSH) stimulation in granulosa cells. In conlusions, leukocytes recruitment by chemokine may play an important role in ovulation, luteinization, and luteolysis, as they have the capacity to secrete cytokines, eicosanoids, vasoactive amines and tissue remodeling enzymes. In addition, the increase in VEGF may contribute to angiogenesis, which in turn would promote various ovulation phenomena as well as follicular growth. It was suggested that these concerted phenomenon contribute to act in human ovulatory process.

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