Interferon β protects against lethal endotoxic and septic shock through SIRT1 upregulation

• Published in: Scientific reports 2014-02, Vol.4 (1), p.4220, Article 4220
• Main Authors: Yoo, Chae-Hwa, Yeom, Ji-Hyun, Heo, Jin-Ju, Song, Eun-Kyung, Lee, Sang-Il, Han, Myung-Kwan
• Format: Article
• Language: English
• Subjects: 42; 42/44; 631/250/255/1318; 631/326/421; Animals; Cytokines - metabolism; Disease Models, Animal; Gene Expression Regulation - drug effects; Humanities and Social Sciences; Inflammation Mediators - metabolism; Interferon-beta - metabolism; Interferon-beta - pharmacology; Janus Kinases - metabolism; Lipopolysaccharides - immunology; Lipopolysaccharides - pharmacology; Macrophages - drug effects; Macrophages - immunology; Macrophages - metabolism; Male; Mice; multidisciplinary; Science; Shock, Septic - genetics; Shock, Septic - immunology; Shock, Septic - metabolism; Shock, Septic - mortality; Shock, Septic - pathology; Signal Transduction - drug effects; Sirtuin 1 - genetics; Sirtuin 1 - metabolism; STAT Transcription Factors - metabolism; Up-Regulation
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep04220

Lipopolysaccharide (LPS), an endotoxin derived from gram-negative bacteria, promotes the secretion of proinflammatory cytokines and mediates endotoxemia through activation of mitogen activated protein kinases, NF-κB and interferon regulatory factor-3. Silent information regulator transcript-1 (SIRT1), an NAD-dependent deacetylase, mediates NF-κB deacetylation and inhibits its function. SIRT1 may affect LPS-mediated signaling pathways and endotoxemia. Here we demonstrate that SIRT1 blocks LPS-induced secretion of interleukin 6 and tumor necrosis factor α in murine macrophages and protects against lethal endotoxic and septic shock in mice. We also demonstrate that interferon β increases SIRT1 expression by activating the Janus kinase – signal transducer and activator of transcription (JAK-STAT) pathway in mouse bone marrow derived macrophages. In vivo treatment of interferon β protects against lethal endotoxic and septic shock, which is abrogated by infection with dominant negative SIRT1-expressing adenovirus. Our work suggests that both SIRT1 and SIRT1-inducing cytokines are useful targets for treating patients with sepsis.