Defective expression of SIRT1 contributes to sustain inflammatory pathways in the gut.
In inflammatory bowel disease (IBD), tissue damage is driven by an excessive immune response, poorly controlled by counter-regulatory mechanisms. SIRT1, a class III NAD+-dependent deacetylase, regulates negatively the expression of various proteins involved in the control of immune-inflammatory pathways, such as Stat3, Smad7, and NF-κB. Here we examined the expression, regulation, and function of SIRT1 in IBD. SIRT1 RNA and protein expression was less pronounced in whole biopsies and lamina propria mononuclear cells (LPMCs) of IBD patients in comparison with normal controls. SIRT1 expression was downregulated in control LPMC by tumor necrosis factor (TNF)-α and interleukin (IL)-21, and upregulated in IBD LPMC by neutralizing TNF-α and IL-21antibodies. Consistently, SIRT1 expression was increased in mucosal samples taken from IBD patients successfully treated with Infliximab. Treatment of IBD LPMC with Cay10591, a specific SIRT1 activator, reduced NF-κB activation and inhibited inflammatory cytokine synthesis, whereas Ex527, an inhibitor of SIRT1, increased interferon (IFN)-γ in control LPMC. SIRT1 was also reduced in mice with colitis induced by 2,4,6-trinitrobenzenesulphonic acid or oxazolone. Cay10591 prevented and cured experimental colitis whereas Ex527 exacerbated disease by modulating T cell-derived cytokine response. Data indicate that SIRT1 is downregulated in IBD patients and colitic mice and suggest that SIRT1 activation can help attenuate inflammatory signals in the gut.
Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy.
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Caruso
Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy.
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Marafini
Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy.
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Franzè
Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy.
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Stolfi
Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy.
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Zorzi
Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy.
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I
Monteleone
Unit of Gastroenterology, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Milan, Italy.
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Caprioli
Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy.
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Colantoni
Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy.
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Sarra
Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy.
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Sedda
Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy.
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Biancone
Department of Surgery, University of Rome "Tor Vergata", Rome, Italy;
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Sileri
Department of Surgery, University of Rome "Tor Vergata", Rome, Italy;
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Sica
Barts and the London School of Medicine and Dentistry, London, UK.
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MacDonald
Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy.
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F
Pallone
Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy.
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G
Monteleone
D000276:Adjuvants, Immunologic / Q000009:adverse effects / Q000494:pharmacology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics / Q000276:immunology*; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000139:chemically induced / Q000188:drug therapy / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D000069285:Infliximab; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D007378:Interleukins / Q000235:genetics / Q000276:immunology; D007422:Intestines / Q000276:immunology* / Q000473:pathology; D008297:Male; D051379:Mice; D008875:Middle Aged; D010081:Oxazolone / Q000009:adverse effects / Q000494:pharmacology; D056564:Sirtuin 1 / Q000235:genetics / Q000276:immunology*; D014302:Trinitrobenzenesulfonic Acid / Q000633:toxicity; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology; D000098546:Interleukin-21
D000276:Adjuvants, Immunologic; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000911:Antibodies, Monoclonal; C573415:IFNG protein, human; D007378:Interleukins; D014409:Tumor Necrosis Factor-alpha; D010081:Oxazolone; D007371:Interferon-gamma; D014302:Trinitrobenzenesulfonic Acid; D000069285:Infliximab; C447939:SIRT1 protein, human; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D000098546:Interleukin-21