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

Abstract

TNF is a key pathogenic cytokine in sepsis. Oberdan Leo and colleagues show that production of TNF during sepsis is regulated by the coenzyme NAD and that inhibition of the enzyme NAMPT, which generates NAD from nicotinamide, can improve survival during sepsis in mice. NAD seems to act via sirtuin-6 to increase the translation of TNF. 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 cytokine1,2. The high expression of nicotinamide phosphoribosyltransferase (Nampt), an enzyme involved in the nicotinamide-dependent NAD biosynthetic pathway, in cells of the immune system3 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 family4, 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.