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

Van Gool, Frédéric and Gallí, Mara and Gueydan, Cyril and Kruys, Véronique and Prevot, Pierre-Paul and Bedalov, Antonio and Mostoslavsky, Raul and Alt, Frederick W and De Smedt, Thibaut and Leo, Oberdan (2009) Intracellular NAD levels regulate tumor necrosis factor protein synthesis in a sirtuin-dependent manner. Nature medicine, 15 (2). pp. 206-10. ISSN 1546-170X

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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.

Item Type: Article or Abstract
Additional Information: This article is available to subscribers only via the URL above.
DOI: 10.1038/nm.1906
PubMed ID: 19151729
PMCID: PMC2845476
Grant Numbers: R01 CA129132-02
Keywords or MeSH Headings: Animals; Enzyme-Linked Immunosorbent Assay; Mice; NAD/metabolism; Nicotinamide Phosphoribosyltransferase/metabolism; Reverse Transcriptase Polymerase Chain Reaction; Tumor Necrosis Factor-alpha/biosynthesis;
Depositing User: Library Staff
Date Deposited: 26 Feb 2010 18:15
Last Modified: 14 Feb 2012 14:43

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