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.
This is a preview of subscription content
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Feldmann, M. & Maini, R.N. Lasker Clinical Medical Research Award. TNF defined as a therapeutic target for rheumatoid arthritis and other autoimmune diseases. Nat. Med. 9, 1245–1250 (2003).
Henson, P.M. Dampening inflammation. Nat. Immunol. 6, 1179–1181 (2005).
Luk, T., Malam, Z. & Marshall, J.C. Pre-B cell colony-enhancing factor (PBEF)/visfatin: a novel mediator of innate immunity. J. Leukoc. Biol. 83, 804–816 (2008).
Saunders, L.R. & Verdin, E. Sirtuins: critical regulators at the crossroads between cancer and aging. Oncogene 26, 5489–5504 (2007).
Ziegler, M. New functions of a long-known molecule. Emerging roles of NAD in cellular signaling. Eur. J. Biochem. 267, 1550–1564 (2000).
Berger, F., Ramirez-Hernandez, M.H. & Ziegler, M. The new life of a centenarian: signalling functions of NAD(P). Trends Biochem. Sci. 29, 111–118 (2004).
Schreiber, V., Dantzer, F., Ame, J.C. & de Murcia, G. Poly(ADP-ribose): novel functions for an old molecule. Nat. Rev. Mol. Cell Biol. 7, 517–528 (2006).
Rongvaux, A. et al. Pre-B-cell colony-enhancing factor, whose expression is up-regulated in activated lymphocytes, is a nicotinamide phosphoribosyltransferase, a cytosolic enzyme involved in NAD biosynthesis. Eur. J. Immunol. 32, 3225–3234 (2002).
Jia, S.H. et al. Pre-B cell colony-enhancing factor inhibits neutrophil apoptosis in experimental inflammation and clinical sepsis. J. Clin. Invest. 113, 1318–1327 (2004).
Ye, S.Q. et al. Pre-B-cell colony-enhancing factor as a potential novel biomarker in acute lung injury. Am. J. Respir. Crit. Care Med. 171, 361–370 (2005).
Busso, N. et al. Pharmacological inhibition of nicotinamide phosphoribosyltransferase/visfatin enzymatic activity identifies a new inflammatory pathway linked to NAD. PLoS ONE 3, e2267 (2008).
Fukuzawa, M. et al. Inhibitory effect of nicotinamide on in vitro and in vivo production of tumor necrosis factor-α. Immunol. Lett. 59, 7–11 (1997).
Ungerstedt, J.S., Blomback, M. & Soderstrom, T. Nicotinamide is a potent inhibitor of proinflammatory cytokines. Clin. Exp. Immunol. 131, 48–52 (2003).
Szabo, C. Nicotinamide: a jack of all trades (but master of none?). Intensive Care Med. 29, 863–866 (2003).
Cuzzocrea, S. Shock, inflammation and PARP. Pharmacol. Res. 52, 72–82 (2005).
Hassa, P.O. & Hottiger, M.O. The functional role of poly(ADP-ribose)polymerase 1 as novel coactivator of NF-κB in inflammatory disorders. Cell. Mol. Life Sci. 59, 1534–1553 (2002).
Oliver, F.J. et al. Resistance to endotoxic shock as a consequence of defective NF-κB activation in poly (ADP-ribose) polymerase-1 deficient mice. EMBO J. 18, 4446–4454 (1999).
Kuhnle, S., Nicotera, P., Wendel, A. & Leist, M. Prevention of endotoxin-induced lethality, but not of liver apoptosis in poly(ADP-ribose) polymerase–deficient mice. Biochem. Biophys. Res. Commun. 263, 433–438 (1999).
Hasmann, M. & Schemainda, I. FK866, a highly specific noncompetitive inhibitor of nicotinamide phosphoribosyltransferase, represents a novel mechanism for induction of tumor cell apoptosis. Cancer Res. 63, 7436–7442 (2003).
Grozinger, C.M., Chao, E.D., Blackwell, H.E., Moazed, D. & Schreiber, S.L. Identification of a class of small molecule inhibitors of the sirtuin family of NAD-dependent deacetylases by phenotypic screening. J. Biol. Chem. 276, 38837–38843 (2001).
Heltweg, B. et al. Antitumor activity of a small-molecule inhibitor of human silent information regulator 2 enzymes. Cancer Res. 66, 4368–4377 (2006).
Mostoslavsky, R. et al. Genomic instability and aging-like phenotype in the absence of mammalian SIRT6. Cell 124, 315–329 (2006).
Michishita, E. et al. SIRT6 is a histone H3 lysine 9 deacetylase that modulates telomeric chromatin. Nature 452, 492–496 (2008).
Ulloa, L. et al. Ethyl pyruvate prevents lethality in mice with established lethal sepsis and systemic inflammation. Proc. Natl. Acad. Sci. USA 99, 12351–12356 (2002).
Inaba, K. et al. Generation of large numbers of dendritic cells from mouse bone marrow cultures supplemented with granulocyte/macrophage colony-stimulating factor. J. Exp. Med. 176, 1693–1702 (1992).
Zerez, C.R., Lee, S.J. & Tanaka, K.R. Spectrophotometric determination of oxidized and reduced pyridine nucleotides in erythrocytes using a single extraction procedure. Anal. Biochem. 164, 367–373 (1987).
APO866 was synthesized and kindly provided by Astellas Pharma. We wish to thank G. de Murcia (formerly at the Ecole Supérieure de Biotechnologie de Strasbourg, Illkirch Cedex) for providing the Parp1-knockout mouse strain and V. Sartorelli (US National Institutes of Health) for providing the pHan-SIRT1 vector (wild-type and mutant forms). This work was supported by The Belgian Program in Interuniversity Poles of Attraction initiated by the Belgian state, the Prime Minister's office, Science Policy Programming, by a Research Concerted Action of the Communauté française de Belgique, by grants from the Direction Générale des Technologies de la Recherche et de l'Energie, Région Wallonne (Belgium), by a grant from the Fonds Jean Brachet and by TopoTarget Switzerland SA. F.V.G. and M.G. have been supported by research grants from the Fonds national de la recherché scientifique (FRS-FNRS), French community of Belgium. The scientific responsibility is assumed by the authors.
T.D.S. was a paid employee of TopoTarget Switzerland S.A. during the completion of this work. Part of the work was performed under a research grant provided by TopoTarget. F.V.G., M.G., O.L. and T.D.S. have made patent applications to the World Intellectual Property Organization (WIPO) pertaining to the possible use of APO866 to treat inflammatory-related disorders.
About this article
Cite this article
Van Gool, F., Gallí, M., Gueydan, C. et al. Intracellular NAD levels regulate tumor necrosis factor protein synthesis in a sirtuin-dependent manner. Nat Med 15, 206–210 (2009). https://doi.org/10.1038/nm.1906
Experimental & Molecular Medicine (2022)
NAD(H)-loaded nanoparticles for efficient sepsis therapy via modulating immune and vascular homeostasis
Nature Nanotechnology (2022)
The potential roles of amino acids and their major derivatives in the management of multiple sclerosis
Amino Acids (2022)
SIRT6 enhances oxidative phosphorylation in breast cancer and promotes mammary tumorigenesis in mice
Cancer & Metabolism (2021)
Nature Reviews Molecular Cell Biology (2021)