title: Intracellular NAD levels regulate tumor necrosis factor protein synthesis in a sirtuin-dependent manner.
abstract: Tumor necrosis factor (TNF) synthesis is known to play a major part in numerous inflammatory disorders, and multiple transcriptional and post-transcriptional regulatory mechanisms have therefore evolved to dampen the production of this key proinflammatory cytokine. The high expression of nicotinamide phosphoribosyltransferase (Nampt), an enzyme involved in the nicotinamide-dependent NAD biosynthetic pathway, in cells of the immune system has led us to examine the potential relationship between NAD metabolism and inflammation. We show here that intracellular NAD concentration promotes TNF synthesis by activated immune cells. Using a positive screen, we have identified Sirt6, a member of the sirtuin family, as the NAD-dependent enzyme able to regulate TNF production by acting at a post-transcriptional step. These studies reveal a previously undescribed relationship between metabolism and the inflammatory response and identify Sirt6 and the nicotinamide-dependent NAD biosynthetic pathway as novel candidates for immunointervention in an inflammatory setting.
authors.affiliation: Laboratoire de Physiologie Animale, Institut de Biologie et Médecine Moléculaire, Université Libre de Bruxelles, 12 rue des Professeur Jeneer et Brachet, 6041 Gosselies, Belgium.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Van Gool
authors.forename: Mara
authors.initials: M
authors.lastname: Gallí
authors.forename: Cyril
authors.initials: C
authors.lastname: Gueydan
authors.forename: Véronique
authors.initials: V
authors.lastname: Kruys
authors.forename: Pierre-Paul
authors.initials: PP
authors.lastname: Prevot
authors.forename: Antonio
authors.initials: A
authors.lastname: Bedalov
authors.forename: Raul
authors.initials: R
authors.lastname: Mostoslavsky
authors.forename: Frederick W
authors.initials: FW
authors.lastname: Alt
authors.forename: Thibaut
authors.initials: T
authors.lastname: De Smedt
authors.forename: Oberdan
authors.initials: O
authors.lastname: Leo
mesh_terms: D000818:Animals; D004797:Enzyme-Linked Immunosorbent Assay; D051379:Mice; D009243:NAD / Q000378:metabolism*; D054409:Nicotinamide Phosphoribosyltransferase / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
chemical_list: D014409:Tumor Necrosis Factor-alpha; D009243:NAD; D054409:Nicotinamide Phosphoribosyltransferase