Novel signaling axis triggered by inflammatory cytokine IL-1 and its relation to fibrosis and cancer

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K06830
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 48040:Medical biochemistry-related
• Research Institution: University of Occupational and Environmental Health, Japan
• Principal Investigator: Hikasa Hiroki 産業医科大学, 医学部, 准教授 (40596839)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 炎症性シグナル / Wnt経路 / IRAK1 / 病態モデルマウス

Outline of Final Research Achievements

Chronic inflammation is closely related to fibrosis and cancer, but its molecular mechanisms are unknown and there are very few useful mouse models of chronic inflammation-related pathologies. We found that in response to IL-1, the downstream kinase IRAK1 activates not only the conventional NFκB pathway but also β-catenin, which is closely related to fibrosis and cancer. This activation of β-catenin by IRAK1 is in a PPPSP motif-dependent and human-specific manner. Furthermore, in order to analyze the function of human IRAK1 in vivo, we succeeded in establishing two types of mice: mice with amino acid substitutions of mouse Irak1 in the genome (humanized mice) and tissue-specific human IRAK1-expressing transgenic mice, and started analysis.

Free Research Field

生化学

Academic Significance and Societal Importance of the Research Achievements

慢性炎症が線維化・がん化を惹起することが知られているが、それらの発症過程を反映する病態モデルマウスは少なく、その機序は不明な点が多い。ゆえに引き金となる鍵分子の同定とそれを利用したモデルマウスの樹立は急務である。さらに、近年の研究動向では、がん分野におけるIRAK1研究はますます注目されることが予想される。それゆえ、本研究を今後も進めることで、慢性炎症からの線維化・がん化のメカニズムの一端が解明できれば、先んじてがん生物学や医学の予防・治療戦略に大きく寄与するものになると期待される。