https://scholars.lib.ntu.edu.tw/handle/123456789/503597
標題: | Anti-inflammatory Activity of MTL-CEBPA, a Small Activating RNA Drug, in LPS-Stimulated Monocytes and Humanized Mice | 作者: | Zhou J. Li H. Xia X. Herrera A. Pollock N. Reebye V. Sodergren M.H. Dorman S. Littman B.H. Doogan D. KAI-WEN HUANG Habib R. Blakey D. Habib N.A. Rossi J.J. |
關鍵字: | anti-inflammation; humanized mice; monocytes; MTL-CEBPA; saRNA; small activating RNA | 公開日期: | 2019 | 出版社: | Cell Press | 卷: | 27 | 期: | 5 | 起(迄)頁: | 999-1016 | 來源出版物: | Molecular Therapy | 摘要: | Excessive or inappropriate inflammatory responses can cause serious and even fatal diseases. The CCAAT/enhancer-binding protein alpha (CEBPA) gene encodes C/EBPα, a transcription factor that plays a fundamental role in controlling maturation of the myeloid lineage and is also expressed during the late phase of inflammatory responses when signs of inflammation are decreasing. MTL-CEBPA, a small activating RNA targeting for upregulation of C/EBPα, is currently being evaluated in a phase 1b trial for treatment of hepatocellular carcinoma. After dosing, subjects had reduced levels of pro-inflammatory cytokines, and we therefore hypothesized that MTL-CEBPA has anti-inflammatory potential. The current study was conducted to determine the effects of C/EBPα saRNA - CEBPA-51 - on inflammation in vitro and in vivo after endotoxin challenge. CEBPA-51 led to increased expression of the C/EBPα gene and inhibition of pro-inflammatory cytokines in THP-1 monocytes previously stimulated by E. coli-derived lipopolysaccharide (LPS). Treatment with MTL-CEBPA in an LPS-challenged humanized mouse model upregulated C/EBPα mRNA, increased neutrophils, and attenuated production of several key pro-inflammatory cytokines, including TNF-α, IL-6, IL-1β, and IFN-γ. In addition, a Luminex analysis of mouse serum revealed that MTL-CEBPA reduced pro-inflammatory cytokines and increased the anti-inflammatory cytokine IL-10. Collectively, the data support further investigation of MTL-CEBPA in acute and chronic inflammatory diseases where this mechanism has pathogenic importance. MTL-CEBPA is a small activating RNA that targets the upregulation of transcription factor C/EBPα, currently being evaluated in a phase 1b trial for treatment of hepatocellular carcinoma. Zhou et al. demonstrate that MTL-CEBPA increases the expression of C/EBPα and displays anti-inflammatory effects in a tissue culture system and a humanized mouse model. ? 2019 The Author(s) |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-85062342718&doi=10.1016%2fj.ymthe.2019.02.018&partnerID=40&md5=2cf242b20cba1291e9c6a8667c6a41bb https://scholars.lib.ntu.edu.tw/handle/123456789/503597 |
ISSN: | 1525-0016 | DOI: | 10.1016/j.ymthe.2019.02.018 | SDG/關鍵字: | bacterium lipopolysaccharide; CCAAT enhancer binding protein alpha; CCAAT enhancer binding protein beta; chemokine receptor CXCR4; colony stimulating factor receptor; double stranded RNA; endotoxin; gamma interferon; interleukin 10; interleukin 1beta; interleukin 6; messenger RNA; programmed death 1 ligand 1; small activating RNA; tumor necrosis factor; unclassified drug; antiinflammatory agent; CCAAT enhancer binding protein; CEBPA protein, human; IL10 protein, human; IL1B protein, human; interleukin 10; interleukin 1beta; lipopolysaccharide; messenger RNA; RNA; tumor necrosis factor; animal experiment; animal model; antiinflammatory activity; Article; blood analysis; cell stimulation; controlled study; cytokine production; human; human cell; in vitro study; in vivo study; inflammation; inhibition kinetics; monocyte; mouse; nonhuman; THP-1 cell line; animal; drug effect; gene expression regulation; genetics; inflammation; metabolism; pathology; Animals; Anti-Inflammatory Agents; CCAAT-Enhancer-Binding Proteins; Gene Expression Regulation; Humans; Inflammation; Interleukin-10; Interleukin-1beta; Lipopolysaccharides; Mice; Monocytes; RNA; RNA, Messenger; Tumor Necrosis Factor-alpha |
顯示於: | 醫學系 |
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