한빛사논문
- 조회960
Harvard Medical School & Massachusetts General Hospital, 현 계명대학교 의과대학
Jong Ho Park 1,2,3, Mahsa Mortaja 1,2, Heehwa G. Son 1,2, Xutu Zhao 1,2, Lauren M. Sloat 1,2, Marjan Azin 1,2, Jun Wang 2, Michael R. Collier 4, Krishna S. Tummala 5,6,7,8,9, Anna Mandinova 2, Nabeel Bardeesy 5,6,7,8, Yevgeniy R. Semenov 4,10, Mari Mino-Kenudson 11 & Shadmehr Demehri 1,2,4,*
1Center for Cancer Immunology, Krantz Family Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
2Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
3Department of Anatomy, School of Medicine, Keimyung University, Daegu, South Korea.
4Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
5Krantz Family Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
6Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA.
7Department of Medicine, Harvard Medical School, Boston, MA, USA.
8Cancer Program, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA.
9Quantitative Biosciences, Merck Research Laboratories, Boston, MA, USA.
10Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Science, Harvard Medical School, Boston, USA.
11Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
*Corresponding author: correspondence to Shadmehr Demehri
Abstract
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 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 inflammation. An FDA-approved drug library screen identifies pitavastatin to effectively suppress IL-33 expression by blocking TBK1 membrane recruitment/activation through the mevalonate pathway inhibition. Accordingly, pitavastatin prevents chronic pancreatitis and its cancer sequela in an IL-33-dependent manner. The IRF3-IL-33 axis is highly active in chronic pancreatitis and its associated pancreatic cancer in humans. Interestingly, pitavastatin use correlates with a significantly reduced risk of chronic pancreatitis and pancreatic cancer in patients. Our findings demonstrate that blocking the TBK1-IRF3-IL-33 signaling axis suppresses cancer-prone chronic inflammation. Statins present a safe and effective prophylactic strategy to prevent chronic inflammation and its cancer sequela.
논문정보
- Research article
- 2024년 05월 (BRIC 등록일 2024-05-31)
- 국내+국외 연구진
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