title: Sirtuin inhibition attenuates the production of inflammatory cytokines in lipopolysaccharide-stimulated macrophages.
abstract: In several inflammatory conditions such as rheumatoid arthritis or sepsis, the regulatory mechanisms of inflammation are inefficient and the excessive inflammatory response leads to damage to the host. Sirtuins are class III histone deacetylases that modulate the activity of several transcription factors that are implicated in immune responses. In this study, we evaluated the impact of sirtuin inhibition on the activation of lipopolysaccharide (LPS)-stimulated J774 macrophages by assessing the production of inflammatory cytokines. The pharmacologic inhibition of sirtuins decreased the production of tumour necrosis factor-alpha (TNF-α) interleukin 6 (IL-6) and Rantes. The reduction of cytokine production was associated with decreased nuclear factor kappa B (NF-κB) activity and inhibitor kappa B alpha (IκBα) phosphorylation while no impact was observed on the phosphorylation status of p38 mitogen-activated kinase (p38 MAPK). This work shows that sirtuin pharmacologic inhibitors are a promising tool for the treatment of inflammatory conditions.
authors.affiliation: Université catholique de Louvain, Louvain Drug Research Institute (LDRI), Pharmaceutics and Drug Delivery Research Group, Brussels B-1200, Belgium.
authors.forename: Cláudia A
authors.initials: CA
authors.lastname: Fernandes
authors.forename: Laurence
authors.initials: L
authors.lastname: Fievez
authors.forename: Audrey M
authors.initials: AM
authors.lastname: Neyrinck
authors.forename: Nathalie M
authors.initials: NM
authors.lastname: Delzenne
authors.forename: Fabrice
authors.initials: F
authors.lastname: Bureau
authors.forename: Rita
authors.initials: R
authors.lastname: Vanbever
mesh_terms: D000818:Animals; D002460:Cell Line; D018946:Chemokine CCL5 / Q000096:biosynthesis; D016207:Cytokines / Q000096:biosynthesis*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D007249:Inflammation / Q000201:enzymology / Q000276:immunology*; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D008264:Macrophages / Q000201:enzymology / Q000276:immunology*; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009281:Naphthalenes / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011744:Pyrimidinones / Q000494:pharmacology; D037761:Sirtuins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D018946:Chemokine CCL5; D016207:Cytokines; D056572:Histone Deacetylase Inhibitors; D015850:Interleukin-6; D008070:Lipopolysaccharides; D016328:NF-kappa B; D009281:Naphthalenes; D011744:Pyrimidinones; D014409:Tumor Necrosis Factor-alpha; C510718:cambinol; D020929:Mitogen-Activated Protein Kinase Kinases; D037761:Sirtuins