3) ゴナドトロピン受容体の機能にその構造及び生理活性物質が及ぼす影響(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)

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  • 岸,裕司
    群馬大学医学部附属病院周産母子センター産科婦人科

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タイトル別名
  • Effects of Physiologically Active Substances on Expression of Gonadotropin Receptors

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The expression of LH receptor (LHR) is one of the major markers of FSH-induced differentiation of granulosa cells. Primary cultures of rat granulosa cells obtained from immature female rats pretreated with estradiol are a frequently used model for studying granulosa cell differentiation. In addition to FSH, many factors, including cytokines are involved in the regulation of LHR expression. Our results indicated that IL-6 enhanced the FSH-induced LHR mRNA expression in a dose-dependent manner. The membrane protein level of LHR increased by FSH was further enhanced by association with IL-6. These enhancement was blocked by the Janus tyrosine kinase pathway inhibitor, but not by the ERK 1/2 inhibitor. So, these enhancement might be mediated by the JAK/signal transducer and activator of transcription pathway. LHR is undetectable in granulosa cells of preantral and small antral follicles. However, after the follicle reaches the preovulatory stage, FSH and estrogen synergistically induce LHR in granulosa cells. It was reported that a preovulatory LH surge in adult female to induce ovulation can cause an acute decrease in LHR mRNA levels, which are subsequently recovered with corpus luteum formation. MicroRNAs (miRNAs) are small noncoding RNAs that interact with mRNAs and trigger either translation repression or RNA cleavage of target genes. We investigated whether miRNA was involved in this down-regulation of the luteinizing hormone receptor (LHR) in rat ovaries. A miRNA microarray was used to analyze the overall miRNA expression profile of rat ovaries in association with the downregulation of LHR mRNA. We found that 23 miRNAs were highly expressed during this period. Combining these results with data from a bioinformatics database, clustering analysis led us to focus on miR-136-3p for further analysis. In both in vivo and in vitro studies, miR-136-3p expression levels were increased at 6h after human chorionic gonadotropin (hCG) administra tion, concurrent with down regulation of LHR mRNA. Moreover, transfection of cultured granulosa cells with miR-136-3p resulted in a significant decrease in LHR mRNA levels in comparison with those of cells transfected with negative control. In contrast, transfection with a miR-136-3p inhibitor increased LHR mRNA levels. These data demonstrated that miR-136-3p participated in the down-regulation of LHR mRNA by binding to LHR mRNA. Menstrual cycle is supported and controlled by complicated mechanisms involving estrogen, growth factors, cytokines, circulating hormones and miRNA.

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