Intracellular NAD levels regulate tumor necrosis factor protein synthesis in a sirtuin-dependent manner.
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.
Van Gool
Frédéric
F
Laboratoire de Physiologie Animale, Institut de Biologie et Médecine Moléculaire, Université Libre de Bruxelles, 12 rue des Professeur Jeneer et Brachet, 6041 Gosselies, Belgium.
Gallí
Mara
M
Gueydan
Cyril
C
Kruys
Véronique
V
Prevot
Pierre-Paul
PP
Bedalov
Antonio
A
Mostoslavsky
Raul
R
Alt
Frederick W
FW
De Smedt
Thibaut
T
Leo
Oberdan
O
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*
D014409:Tumor Necrosis Factor-alpha; D009243:NAD; D054409:Nicotinamide Phosphoribosyltransferase