The in vivo roles of biosynthetic enzyme and receptors for leukotriene B4

2020 Fiscal Year Final Research Report

• Project/Area Number: 18H02627
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 49010:Pathological biochemistry-related
• Research Institution: Juntendo University
• Principal Investigator: Yokomizo Takehiko 順天堂大学, 医学(系)研究科(研究院), 教授 (60302840)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: 生理活性脂質 / 生体分子 / 遺伝子改変マウス / 炎症性疾患

Outline of Final Research Achievements

The following experiments were conducted to clarify the in vivo roles of the biosynthetic enzyme (LTA4H) and receptors (BLT1 and BLT2) for the biologically active lipid leukotriene B4(LTB4). We generated dendritic cell (DC)-specific BLT1-deficient mice, and LTA4H E297Q knock-in mice lacking only aminopeptidase activity. Using these mice, I obtained the following results 1) I identified dendritic cell subsets defined by BLT1 expression and determined their different roles in inflammatory disease models. BLT1-high DC enhances inflammation by staying at the inflammatory lesion and secreting IL-12, and BLT1-low DC migrates to draining lymph node and stimulates T cell proliferation by secreting IL-2. 2) In LTA4H-deficient mice, thyroid hormone secretion is increased, resulting in a "thin" phenotype, which is dependent on the loss of aminopeptidase activity of LTA4H, not on the loss of LTB4-producing activity. LTA4 aminopeptidase activity somehow inhibits thyroid hormones production/release.

Free Research Field

生化学・薬理学

Academic Significance and Societal Importance of the Research Achievements

ロイコトリエンB4は強力な炎症作用を有する生理活性脂質であり、その産生酵素や受容体は炎症性疾患の新規治療標的として注目されている。本研究は主としてロイコトリエンB4関連分子の遺伝子欠損マウスの解析を通じて、炎症性疾患の発症と増悪におけるロイコトリエンB4関連分子の関連を明らかにした研究である。本研究は将来的に、ヒトの炎症性疾患の新規創薬に繋がる可能性をもつ研究である。