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

Abstract

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-kappa B, and interferon regulatory factor-3. Silent information regulator transcript-1 (SIRT1), an NAD-dependent deacetylase, mediates NF-kappa B 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 alpha in murine macrophages, and protects against lethal endotoxic and septic shock in mice. We also demonstrate that interferon beta 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 beta 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.