title: Interferon β 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-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.
authors.affiliation: 1] Department of Microbiology, Chonbuk National University Medical School, Jeonju 561-182, Republic of Korea [2].
authors.forename: Chae-Hwa
authors.initials: CH
authors.lastname: Yoo
authors.affiliation: 1] Department of Microbiology, Chonbuk National University Medical School, Jeonju 561-182, Republic of Korea [2].
authors.forename: Ji-Hyun
authors.initials: JH
authors.lastname: Yeom
authors.affiliation: Department of Microbiology, Chonbuk National University Medical School, Jeonju 561-182, Republic of Korea.
authors.forename: Jin-Ju
authors.initials: JJ
authors.lastname: Heo
authors.affiliation: Department of Microbiology, Chonbuk National University Medical School, Jeonju 561-182, Republic of Korea.
authors.forename: Eun-Kyung
authors.initials: EK
authors.lastname: Song
authors.affiliation: Department of Internal Medicine, Institute of Health Science, Gyeongsang National University College of Medicine, Jinju 660-702, Republic of Korea.
authors.forename: Sang-Il
authors.initials: SI
authors.lastname: Lee
authors.affiliation: 1] Department of Microbiology, Chonbuk National University Medical School, Jeonju 561-182, Republic of Korea [2] Institute for Medical Science, Chonbuk National University Medical School, Jeonju 561-182, Republic of Korea.
authors.forename: Myung-Kwan
authors.initials: MK
authors.lastname: Han
mesh_terms: D000818:Animals; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D018836:Inflammation Mediators / Q000378:metabolism; D016899:Interferon-beta / Q000378:metabolism* / Q000494:pharmacology; D053612:Janus Kinases / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D050791:STAT Transcription Factors / Q000378:metabolism; D012772:Shock, Septic / Q000235:genetics* / Q000276:immunology / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D056564:Sirtuin 1 / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D050791:STAT Transcription Factors; D016899:Interferon-beta; D053612:Janus Kinases; D056564:Sirtuin 1