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-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.
Highlights
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-kB, and interferon regulatory factor-3
Over 95% of the bone marrow-derived macrophages (BMDMs) were double positive for CD11b and F4/80, macrophage surface markers (Fig. 1A), indicating successful differentiation into macrophages
We demonstrated that Silent information regulator transcript-1 (SIRT1) expression inhibits LPS-induced secretion of proinflammatory cytokines and protects against endotoxemia and sepsis
Summary
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-kB, and interferon regulatory factor-3. TLRs associate with many cytoplasmic adaptor proteins containing TIR domains, including myeloid differentiation factor 88 (MyD88), MyD88-adaptor-like/TIRassociated protein (MAL/TIRAP), TIR-domain-containing adaptor-inducing interferon(IFN)-b (TRIF), and Toll-receptor-associated molecule (TRAM)[5,6]. This association results in the recruitment and activation of IRAK1 and IRAK4, which form a complex with TRAF6 to activate TAK1 and IKK5. The MyD88-dependent pathway, which is common to all TLRs except TLR3, leads to the activation of interferon regulatory factor (IRF)-5, mitogen activated protein kinase (MAPK), NF-kB, and AP-1 This results in the expression of proinflammatory chemokines and cytokines such as tumor necrosis factor (TNF-a), interleukin-1 (IL-1), IL-6, and IL-b. SIRT1 deacetylates Lys[310] of RelA/p65 subunits of NF-kB and inhibits www.nature.com/scientificreports both its transcriptional activity and the release of inflammatory cytokines mediated by NF-kB15, suggesting that SIRT1 may regulate the macrophage inflammatory response
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