1. Intracellular NAD levels regulate tumor necrosis factor protein synthesis in a sirtuin-dependent manner
- Author
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Véronique Kruys, Cyril Gueydan, Frédéric Van Gool, Thibaut De Smedt, Raul Mostoslavsky, Oberdan Leo, Mara Galli, Pierre Paul Prevot, Frederick W. Alt, and Antonio Bedalov
- Subjects
SIRT6 ,biology ,Nicotinamide phosphoribosyltransferase ,Inflammation ,General Medicine ,General Biochemistry, Genetics and Molecular Biology ,Proinflammatory cytokine ,Cell biology ,chemistry.chemical_compound ,Immune system ,chemistry ,Biochemistry ,Sirtuin ,medicine ,biology.protein ,Tumor necrosis factor alpha ,NAD+ kinase ,medicine.symptom - 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.
- Published
- 2009