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

Yoo CH, Yeom JH, Heo JJ, Song EK, Lee SI, Han MK - Sci Rep (2014)

Bottom Line: 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.Our work suggests that both SIRT1 and SIRT1-inducing cytokines are useful targets for treating patients with sepsis.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Microbiology, Chonbuk National University Medical School, Jeonju 561-182, Republic of Korea [2].

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.

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LPS increases SIRT1 expression by IFN-β mediated signaling pathway in BMDMs.(A) Dose dependant effect of IFN-β on SIRT1 protein expression. BMDMs were incubated with the indicated doses of IFN-β for 24 h. A western blot was performed for SIRT1 with β-actin as a loading control. (B) The effect of IFN-β neutralizing antibody on LPS-induced SIRT1 expression. BMDMs were treated with LPS in the presence or absence of IFN-β neutralizing antibody (1 μg/mL) for 24 h. (C) The effect of various inhibitors for signal transduction on IFN-β-induced SIRT1 expression. BMDMs were pretreated with vehicle (DMSO), 10 μM PD098059 (PD), 10 μM SB203580 (SB), 10 μM SP600125 (SP), 10 μM PDTC, 1 μM wortmannin (WT), 5 μM LY294002 (LY), 5 μM JAK1 inhibitor (JAK1), and 10 μM JAK3 inhibitor (JAK3) for 1 h and further treated with 100 U/ml IFN-β for 24 h. Full-length blots are presented in Supplementary Figure S3–S5. The Western blot shown is a representative of three independent experiments.
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f2: LPS increases SIRT1 expression by IFN-β mediated signaling pathway in BMDMs.(A) Dose dependant effect of IFN-β on SIRT1 protein expression. BMDMs were incubated with the indicated doses of IFN-β for 24 h. A western blot was performed for SIRT1 with β-actin as a loading control. (B) The effect of IFN-β neutralizing antibody on LPS-induced SIRT1 expression. BMDMs were treated with LPS in the presence or absence of IFN-β neutralizing antibody (1 μg/mL) for 24 h. (C) The effect of various inhibitors for signal transduction on IFN-β-induced SIRT1 expression. BMDMs were pretreated with vehicle (DMSO), 10 μM PD098059 (PD), 10 μM SB203580 (SB), 10 μM SP600125 (SP), 10 μM PDTC, 1 μM wortmannin (WT), 5 μM LY294002 (LY), 5 μM JAK1 inhibitor (JAK1), and 10 μM JAK3 inhibitor (JAK3) for 1 h and further treated with 100 U/ml IFN-β for 24 h. Full-length blots are presented in Supplementary Figure S3–S5. The Western blot shown is a representative of three independent experiments.

Mentions: It has been demonstrated that LPS induces IFN-β expression via the activation of the TLR4 signaling pathway, leading to the activation of the JAK-STAT signaling pathway22. This suggests the possibility that LPS induces SIRT1 by IFN-β mediated activation of JAK-STAT signaling pathway. IFN-β treatment induced SIRT1 expression at the dose of 100 U/ml (Fig. 2A). IFN-β-neutralizing antibody blocked LPS-induced SIRT1 expression (Fig. 2B), demonstrating that IFN-β mediates LPS-induced SIRT1 expression. Pretreatment with PD098059, SB203580, SP600125 and PDTC increased IFN-β-induced SIRT1 expression, suggesting negative regulation of IFN-β-induced SIRT1 expression by MAPKs and NF-kB in BMDMs (Fig. 2C). Pretreatment with wortmannin, LY294002 or JAK3 inhibitor did not alter IFN-β-induced SIRT1 expression (Fig. 2C). However, pretreatment with JAK1 inhibitor abrogated IFN-β-induced SIRT1 expression (Fig. 2C). These results suggest that, like LPS-induced SIRT1 expression, IFN-β is a downstream signal that leads to SIRT1 expression through the activation of the JAK-STAT.


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

Yoo CH, Yeom JH, Heo JJ, Song EK, Lee SI, Han MK - Sci Rep (2014)

LPS increases SIRT1 expression by IFN-β mediated signaling pathway in BMDMs.(A) Dose dependant effect of IFN-β on SIRT1 protein expression. BMDMs were incubated with the indicated doses of IFN-β for 24 h. A western blot was performed for SIRT1 with β-actin as a loading control. (B) The effect of IFN-β neutralizing antibody on LPS-induced SIRT1 expression. BMDMs were treated with LPS in the presence or absence of IFN-β neutralizing antibody (1 μg/mL) for 24 h. (C) The effect of various inhibitors for signal transduction on IFN-β-induced SIRT1 expression. BMDMs were pretreated with vehicle (DMSO), 10 μM PD098059 (PD), 10 μM SB203580 (SB), 10 μM SP600125 (SP), 10 μM PDTC, 1 μM wortmannin (WT), 5 μM LY294002 (LY), 5 μM JAK1 inhibitor (JAK1), and 10 μM JAK3 inhibitor (JAK3) for 1 h and further treated with 100 U/ml IFN-β for 24 h. Full-length blots are presented in Supplementary Figure S3–S5. The Western blot shown is a representative of three independent experiments.
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Related In: Results  -  Collection

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f2: LPS increases SIRT1 expression by IFN-β mediated signaling pathway in BMDMs.(A) Dose dependant effect of IFN-β on SIRT1 protein expression. BMDMs were incubated with the indicated doses of IFN-β for 24 h. A western blot was performed for SIRT1 with β-actin as a loading control. (B) The effect of IFN-β neutralizing antibody on LPS-induced SIRT1 expression. BMDMs were treated with LPS in the presence or absence of IFN-β neutralizing antibody (1 μg/mL) for 24 h. (C) The effect of various inhibitors for signal transduction on IFN-β-induced SIRT1 expression. BMDMs were pretreated with vehicle (DMSO), 10 μM PD098059 (PD), 10 μM SB203580 (SB), 10 μM SP600125 (SP), 10 μM PDTC, 1 μM wortmannin (WT), 5 μM LY294002 (LY), 5 μM JAK1 inhibitor (JAK1), and 10 μM JAK3 inhibitor (JAK3) for 1 h and further treated with 100 U/ml IFN-β for 24 h. Full-length blots are presented in Supplementary Figure S3–S5. The Western blot shown is a representative of three independent experiments.
Mentions: It has been demonstrated that LPS induces IFN-β expression via the activation of the TLR4 signaling pathway, leading to the activation of the JAK-STAT signaling pathway22. This suggests the possibility that LPS induces SIRT1 by IFN-β mediated activation of JAK-STAT signaling pathway. IFN-β treatment induced SIRT1 expression at the dose of 100 U/ml (Fig. 2A). IFN-β-neutralizing antibody blocked LPS-induced SIRT1 expression (Fig. 2B), demonstrating that IFN-β mediates LPS-induced SIRT1 expression. Pretreatment with PD098059, SB203580, SP600125 and PDTC increased IFN-β-induced SIRT1 expression, suggesting negative regulation of IFN-β-induced SIRT1 expression by MAPKs and NF-kB in BMDMs (Fig. 2C). Pretreatment with wortmannin, LY294002 or JAK3 inhibitor did not alter IFN-β-induced SIRT1 expression (Fig. 2C). However, pretreatment with JAK1 inhibitor abrogated IFN-β-induced SIRT1 expression (Fig. 2C). These results suggest that, like LPS-induced SIRT1 expression, IFN-β is a downstream signal that leads to SIRT1 expression through the activation of the JAK-STAT.

Bottom Line: 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.Our work suggests that both SIRT1 and SIRT1-inducing cytokines are useful targets for treating patients with sepsis.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Microbiology, Chonbuk National University Medical School, Jeonju 561-182, Republic of Korea [2].

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.

Show MeSH
Related in: MedlinePlus