Journal article
RNA interference targeting Fas protects mice from fulminant hepatitis
Nature medicine, Vol.9(3), pp.347-351
03/2003
DOI: 10.1038/nm828
PMID: 12579197
Abstract
RNA interference (RNAi) is a powerful tool to silence gene expression post-transcriptionally. However, its potential to treat or prevent disease remains unproven. Fas-mediated apoptosis is implicated in a broad spectrum of liver diseases, where inhibiting hepatocyte death is life-saving. We investigated the in vivo silencing effect of small interfering RNA (siRNA) duplexes targeting the gene Fas (also known as Tnfrsf6), encoding the Fas receptor, to protect mice from liver failure and fibrosis in two models of autoimmune hepatitis. Intravenous injection of Fas siRNA specifically reduced Fas mRNA levels and expression of Fas protein in mouse hepatocytes, and the effects persisted without diminution for 10 days. Hepatocytes isolated from mice treated with Fas siRNA were resistant to apoptosis when exposed to Fas-specific antibody or co-cultured with concanavalin A (ConA)-stimulated hepatic mononuclear cells. Treatment with Fas siRNA 2 days before ConA challenge abrogated hepatocyte necrosis and inflammatory infiltration and markedly reduced serum concentrations of transaminases. Administering Fas siRNA beginning one week after initiating weekly ConA injections protected mice from liver fibrosis. In a more fulminant hepatitis induced by injecting agonistic Fas-specific antibody, 82% of mice treated with siRNA that effectively silenced Fas survived for 10 days of observation, whereas all control mice died within 3 days. Silencing Fas expression with RNAi holds therapeutic promise to prevent liver injury by protecting hepatocytes from cytotoxicity.
Details
- Title: Subtitle
- RNA interference targeting Fas protects mice from fulminant hepatitis
- Creators
- Erwei Song - Center for Blood Research and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USASang-Kyung LeeJie WangNedim InceNengtai OuyangJun MinJisheng ChenPremlata ShankarJudy Lieberman
- Resource Type
- Journal article
- Publication Details
- Nature medicine, Vol.9(3), pp.347-351
- DOI
- 10.1038/nm828
- PMID
- 12579197
- ISSN
- 1078-8956
- eISSN
- 1546-170X
- Grant note
- AI45306 / NIAID NIH HHS AI42510 / NIAID NIH HHS AI49792 / NIAID NIH HHS AI45406 / NIAID NIH HHS
- Language
- English
- Date published
- 03/2003
- Academic Unit
- Gastroenterology and Hepatology; Internal Medicine
- Record Identifier
- 9984094491502771
Metrics
28 Record Views