Park Jong Ho, Mortaja Mahsa, Son Heehwa, Azin Marjan, Wang Jun, Collier Michael, Mandinova Anna, Semenov Yevgeniy, Mino-Kenudson Mari, Demehri Shadmehr
Massachusetts General Hospital.
Res Sq. 2023 Jan 12:rs.3.rs-2318750. doi: 10.21203/rs.3.rs-2318750/v1.
Chronic inflammation is a major cause of cancer worldwide. Interleukin 33 (IL-33) is a critical initiator of cancer-prone chronic inflammation; however, its induction mechanism by the environmental causes of chronic inflammation is unknown. Herein, we demonstrate that Toll-like receptor (TLR)3/4-TBK1-IRF3 pathway activation links environmental insults to IL-33 induction in the skin and pancreas. FDA-approved drug library screen identified pitavastatin as an effective IL-33 inhibitor by blocking TBK1 membrane recruitment/activation through the mevalonate pathway inhibition. Accordingly, pitavastatin prevented chronic pancreatitis and its cancer sequela in an IL-33-dependent manner. IRF3-IL-33 axis was highly active in chronic pancreatitis and its associated pancreatic cancer in humans. Interestingly, pitavastatin use correlated with a significantly reduced risk of chronic pancreatitis and pancreatic cancer in patients. Our findings demonstrate that blocking the TBK1-IRF3 signaling pathway suppresses IL-33 expression and cancer-prone chronic inflammation. Statins present a safe and effective therapeutic strategy to prevent chronic inflammation and its cancer sequela.
慢性炎症是全球癌症的主要病因。白细胞介素33（IL-33）是易引发癌症的慢性炎症的关键启动因子；然而，其由慢性炎症的环境因素引发的机制尚不清楚。在此，我们证明Toll样受体（TLR）3/4-TBK1-IRF3信号通路的激活将环境损伤与皮肤和胰腺中IL-33的诱导联系起来。FDA批准的药物文库筛选确定匹伐他汀是一种有效的IL-33抑制剂，它通过抑制甲羟戊酸途径来阻断TBK1的膜募集/激活。相应地，匹伐他汀以IL-33依赖的方式预防慢性胰腺炎及其癌症后遗症。在人类慢性胰腺炎及其相关胰腺癌中，IRF3-IL-33轴高度活跃。有趣的是，患者使用匹伐他汀与慢性胰腺炎和胰腺癌风险显著降低相关。我们的研究结果表明，阻断TBK1-IRF3信号通路可抑制IL-33表达和易引发癌症的慢性炎症。他汀类药物是预防慢性炎症及其癌症后遗症的一种安全有效的治疗策略。
