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Intracellular NAD levels regulate tumor necrosis factor protein synthesis in a sirtuin-dependent manner

Authors :
Van Gooll, Frederic
Galli, Mara
Gueydan, Cyril
Kruys, Veronique
Prevot, Pierre-Paul
Bedalov, Antonio
Mostoslavsky, Raul
Alt, Frederick W.
De Smedt, Thibaut
Leo, Oberdan
Source :
Nature Medicine. Feb, 2009, Vol. 15 Issue 2, p206, 5 p.
Publication Year :
2009

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 (1,2). The high expression of nicotinamide phosphoribosyltransferase (Nampt), an enzyme involved in the nicotinamide-dependent NAD biosynthetic pathway, in cells of the immune system (3) 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 (4), 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.<br />NAD is an essential cofactor regulating numerous cellular metabolic pathways that has been recently recognized as a substrate for a growing number of NAD-dependent enzymes with multiple roles in cellular [...]

Details

Language :
English
ISSN :
10788956
Volume :
15
Issue :
2
Database :
Gale General OneFile
Journal :
Nature Medicine
Publication Type :
Academic Journal
Accession number :
edsgcl.194904959