Epigenetic suppression of SOCS3 and enhanced activation of STAT3 in activated hepatic stellate cells.

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K07944
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: Nagasaki University
• Principal Investigator: Nakao Kazuhiko 長崎大学, 医歯薬学総合研究科(医学系), 教授 (00264218)
• Co-Investigator(Kenkyū-buntansha): 宮明 寿光 長崎大学, 医歯薬学総合研究科(医学系), 准教授 (20437891) ; 三馬 聡 長崎大学, 病院(医学系), 講師 (30437892)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 肝星細胞 / TGF-β / SOCS3 / STAT3 / DNA methyltransferase

Outline of Final Research Achievements

When IL-6 was added to a hepatic stellate cell line activated with TGF-β, JAK2-STAT3 signal activation was observed, and αSMA expression and type I collagen production were also increased. In activated hepatic stellate cells, SOCS3 expression was decreased, suggesting that the negative feedback pathway mediated by SOCS3 was not activated. Treatment with the demethylating agent 5-aza restored SOCS3 expression, and addition of IL-6 also induced SOCS3 expression, suggesting that the SOCS3 gene is epigenetically suppressed in activated hepatic stellate cells. It was suggested that methylation sites exist in the SOCS3 gene promoter region in activated hepatic stellate cells.

Free Research Field

消化器内科学

Academic Significance and Societal Importance of the Research Achievements

本研究により、IL-6/JAK2/STAT3に対して抑制的に作用するSOCS3の発現が、TGF-βで誘導されるSOCS3遺伝子のメチル化によって持続的に抑制され、STAT3の恒常的活性化が起き、星細胞の持続的活性化が維持されるという仮説の妥当性が示された。よって、線維芽細胞の持続的活性化が生じている強皮症と同じ機序が肝星細胞の活性化でも生じており、SOCS3の発現を調整することで肝星細胞の活性化を制御できることが示唆された。本研究結果は、肝星細胞活性化抑制を介した肝線維化の抑制という、慢性肝疾患の進行防止と治療に向けた研究へ繋がり、その意義は大きい。