Molecular mechanism of pregnancy failure with aging: possible role of inflammasome

• Project/Area Number: 15K07783
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Integrative animal science
• Research Institution: Tokyo University of Agriculture
• Principal Investigator: SHIRASUNA Koumei 東京農業大学, 農学部, 准教授 (20552780)
• Co-Investigator(Kenkyū-buntansha): 岩田 尚孝 東京農業大学, 農学部, 教授 (50385499) ; 桑山 岳人 東京農業大学, 農学部, 教授 (40215124)
• Project Period (FY): 2015-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2017: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2016: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 加齢 / 妊娠 / 卵管 / 子宮 / 炎症 / 免疫 / 老化

Outline of Final Research Achievements

In this study, we hypothesized that the decrease in pregnancy rate might be caused by the fall of the oviduct and uterine function and the excessive inflammatory state with aging, and the cow was verified as a model. From analysis of next-generation sequencers, old-derived oviduct cells had higher expression of inflammation-related gene groups (IL-1, S100A, etc.) than younger-derived oviduct cells. Aging induction candidate factors has been shown to induce inflammation of oviduct cells and abnormalities of fertilization and embryogenesis.

Academic Significance and Societal Importance of the Research Achievements

加齢に伴う過剰な老化因子の蓄積が子宮・卵管細胞の慢性炎症を引き起こした。また、老化誘導候補因子が細胞の機能異常や発生異常を引き起こすことが分かった。以上から、妊娠に重要な卵管・子宮は加齢に伴い機能異常が起きることが判明し、その機序の一端を明らかにできたことから、これらの成果が老化制御法や治療法の開発に繋がることが期待できる。

Research Products

• [Journal Article] Oxygen concentration modulates cellular senescence and autophagy in human trophoblast cells (2018)
  • Author(s): Seno K, Tanikawa N, Takahashi H, Ohkuchi A, Suzuki H, Matsubara S, Iwata H, Kuwayama T, Shirasuna K
  • Journal Title: Am J Reprod Immunol Volume: 79 Issue: 6
  • DOI: 10.1111/aji.12826
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Age-related changes in the bovine corpus luteum function and progesterone secretion (2018)
  • Author(s): Hori Konomi、Matsuyama Shuichi、Nakamura Sho、Iwata Hisataka、Kuwayama Takehito、Miyamoto Akio、Shirasuna Koumei
  • Journal Title: Reproduction in Domestic Animals Volume: 54 Issue: 1 Pages: 23-30
  • DOI: 10.1111/rda.13303
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Interferon tau regulates cytokine production and cellular function in human trophoblast cell line (2017)
  • Author(s): Tanikawa N, Seno K, Kawahara-Miki R, Kimura K, Matsuyama S, Iwata H, Kuwayama T, Shirasuna K
  • Journal Title: J Interferon & Cytokine Research Volume: 37 Issue: 10 Pages: 456-466
  • DOI: 10.1089/jir.2017.0057
  • Peer Reviewed
• [Journal Article] Age-associated mRNA expression changes in bovine endometrial cells in vitro (2017)
  • Author(s): Tanikawa N, Ohtsu A, Kawahara-Miki R, Kimura K, Matsuyama S, Iwata H, Kuwayama T, Shirasuna K
  • Journal Title: Reprod Biol Endocrinol Volume: 15 Issue: 1 Pages: 63-63
  • DOI: 10.1186/s12958-017-0284-z
  • Peer Reviewed
• [Journal Article] Advanced glycation end products regulate interleukin-1β production in human placenta (2017)
  • Author(s): Seno K, Sase S, Ozeki A, Takahashi H, Ohkuchi A, Suzuki H, Matsubara S, Iwata H, Kuwayama T, Shirasuna K
  • Journal Title: Journal of Reproduction and Development Volume: 63 Issue: 4 Pages: 401-408
  • DOI: 10.1262/jrd.2017-032
  • NAID: 130005982808
  • ISSN: 0916-8818, 1348-4400
  • Peer Reviewed / Open Access
• [Journal Article] Palmitic acid stimulates interleukin-8 via the TLR4/NF-kB/ROS pathway and induces mitochondrial dysfunction in bovine oviduct epithelial cells. (2017)
  • Author(s): Ohtsu A, Tanaka H, Seno K, Iwata H, Kuwayama T, Shirasuna K
  • Journal Title: Am J Reprod Immunol Volume: 印刷中 Issue: 6
  • DOI: 10.1111/aji.12642
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Age-dependent changes in inflammation and extracellular matrix in bovine oviduct epithelial cells during post-ovulatory phase. (2016)
  • Author(s): Tanaka H, Ohtsu A, Shiratsuki S, Kawahara-Miki R, Iwata H, Kuwayama T, Shirasuna K
  • Journal Title: Mol Reprod Dev Volume: 83 Issue: 9 Pages: 815-826
  • DOI: 10.1002/mrd.22693
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] AGEs and HMGB1 Increase Inflammatory Cytokine Production from Human Placental Cells, Resulting in an Enhancement of Monocyte Migration. (2016)
  • Author(s): Shirasuna K, Seno K, Ohtsu A, Shiratsuki S, Ohkuchi A, Suzuki H, Matsubara S, Nagayama S, Iwata H, Kuwayama T.
  • Journal Title: Am J Reprod Immunol Volume: 75 Issue: 5 Pages: 557-568
  • DOI: 10.1111/aji.12506
  • Peer Reviewed
• [Journal Article] Palmitic acid induces interleukin-1beta secretion via NLRP3 inflammasomes and inflammatory responses through ROS production in human placental cells. (2016)
  • Author(s): Shirasuna K, Takano T, Seno K, Ohtsu A, Karasawa T, Takahashi M, Ohkuchi A, Suzuki H, Matsubara S, Iwata H, Kuwayama T.
  • Journal Title: J Reprod Immunol Volume: 116 Pages: 104-112
  • DOI: 10.1016/j.jri.2016.06.001
  • Peer Reviewed
• [Journal Article] 加齢と妊娠成立機構：免疫機能の重要性 (2015)
  • Author(s): 白砂 孔明, 岩田 尚孝
  • Journal Title: 日本胚移植学雑誌 (Japanese Journal of Embryo Transfer) Volume: 37 Pages: 133-137
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] 加齢がウシ卵管上皮細胞の細胞老化や加齢性炎症に及ぼす影響 (2018)
  • Author(s): 中村悠稀, 市川遥翔，水野佳穂，岩田尚孝，桑山岳人，白砂孔明
  • Organizer: 第110回日本繁殖生物学会
• [Presentation] ウシ末梢血多核球と単核球におけるIFNT応答性と作用の比較検討 (2018)
  • Author(s): 鬼沢優里，江口空，舟島なつみ，作本亮介，坂上信忠，岩田尚孝，桑山岳人，白砂孔明
  • Organizer: 第110回日本繁殖生物学会
• [Presentation] ウシ脾臓細胞におけるインターフェロンτの免疫細胞分化誘導の可能性の検討 (2018)
  • Author(s): 江口空，鬼沢優里，舟島なつみ，宗像祥久，作本亮介，坂上信忠，岩田尚孝，桑山岳人，白砂孔明
  • Organizer: 第110回日本繁殖生物学会
• [Presentation] Inflammatory-related factors are activated depending on aging in bovine oviduct epithelial cells. (2017)
  • Author(s): Shirasuna K, Tanaka H, Ohtsu A, Nakamura Y, Kawahara-Miki R, Iwata H, Kuwayama T
  • Organizer: 4th World Congress of Reproductive Biology
  • Int'l Joint Research
• [Presentation] Effect of aging on the corpus luteum function in beef and dairy cows. (2017)
  • Author(s): Hori K, Matsuyama S, Nakamura S, Naito A, Matsushita M, Arihara W, Kawahara H, Iwata H, Kuwayama T, Miyamoto A Shirasuna K
  • Organizer: 4th World Congress of Reproductive Biology
  • Int'l Joint Research
• [Presentation] Inflammation, interferon signaling, and cell cycle-related genes are changed with aging in bovine endometrial cells. (2017)
  • Author(s): Tanikawa N, Ohtsu A, Kawahara-Miki R, Kimura K, Matsuyama S, Iwata H, Kuwayama T, Miyamoto A Shirasuna K
  • Organizer: 4th World Congress of Reproductive Biology
  • Int'l Joint Research
• [Presentation] ヒト絨毛細胞株(Sw71)においてパルミチン酸はNLRP3インフラマソームを活性化する (2016)
  • Author(s): 妹尾琴実、鷹野弘樹、大津彩華、大口昭英、唐澤直義、高橋将文、岩田尚孝、桑山岳人、白砂孔明
  • Organizer: 第31回日本生殖免疫学会
  • Place of Presentation: 神戸国際会議場（兵庫県 神戸市）
  • Year and Date: 2016-12-02
• [Presentation] 軽度の低酸素環境がヒト栄養膜細胞株の炎症応答やオートファジーに及ぼす影響 (2016)
  • Author(s): 白砂孔明，島村成美，後藤千尋，妹尾琴実，大口昭英，岩田尚孝，桑山岳人
  • Organizer: 第24回日本胎盤学会
  • Place of Presentation: アバローム紀ノ國（和歌山県 和歌山市）
  • Year and Date: 2016-11-25
• [Presentation] ウシの加齢に伴う黄体機能の変化についての検討 (2016)
  • Author(s): 堀 このみ, 内藤 あおば，松下 麻友美，大津 彩華，岩田 尚孝，桑山 岳人，宮本 明夫，白砂 孔明
  • Organizer: 第109回日本繁殖生物学会
  • Place of Presentation: 麻布大学（神奈川県 相模原市）
  • Year and Date: 2016-09-11
• [Presentation] パルミチン酸はウシ卵管上皮細胞の炎症応答を惹起する (2016)
  • Author(s): 大津 彩華, 田中 葉月，白築 章吾，岩田 尚孝，桑山 岳人，白砂 孔明
  • Organizer: 第109回日本繁殖生物学会
  • Place of Presentation: 麻布大学（神奈川県 相模原市）
  • Year and Date: 2016-09-11
• [Presentation] ウシ卵管上皮細胞における年齢依存性変化 (2016)
  • Author(s): 田中 葉月,大津 彩華，白築 章吾，岩田 尚孝，桑山 岳人，白砂 孔明
  • Organizer: 第109回日本繁殖生物学会
  • Place of Presentation: 麻布大学（神奈川県 相模原市）
  • Year and Date: 2016-09-11
• [Presentation] AGEおよびHMGB1はヒト絨毛膜細胞株（Sw71）において炎症反応を惹起する (2015)
  • Author(s): 妹尾琴実，白砂孔明，島村成美，白築章吾，大口昭英，岩田尚孝，桑山岳人．
  • Organizer: 第23回日本胎盤学会
  • Place of Presentation: 東京
  • Year and Date: 2015-11-05
• [Remarks] 東京農業大学 動物生殖学研究室HP
  • URL: http://hansyokuken.wix.com/hansyokuken
• [Remarks] 東京農業大学 家畜繁殖学研究室HP
  • URL: http://hansyokuken.wix.com/hansyokuken