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

Nature Medicine volume 15, pages 206–210 (2009)Cite this article

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 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.

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Figure 1: Intracellular NAD levels determine TNF production capacities.
Figure 2: Immunomodulatory properties of sirtuin inhibitors.
Figure 3: Sirtuin inhibitors affect TNF production at a post-transcriptional step.
Figure 4: SIRT6 regulates TNF protein synthesis.

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Acknowledgements

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.

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Author notes

  1. Pierre-Paul Prevot, Raul Mostoslavsky & Thibaut De Smedt

    Present address: Present addresses: Université Catholique de Louvain, Christian de Duve Institute of Cellular Pathology Hormone and Metabolic Research Unit, Avenue Hippocrate 75 /7529, B-1200 Brussels, Belgium (P.-P.P.); Department of Medicine, Massachusetts General Hospital Cancer Center, Harvard Medical School, 185 Cambridge Street, Boston, Massachusetts 02114, USA (R.M.); Addex Pharmaceuticals, 12 chemin des Aulx Plan-Les-Ouates, CH-1228 Geneva, Switzerland (T.D.S.).,

  2. Frédéric Van Gool and Mara Gallí: These authors contributed equally to this work.

Authors and Affiliations

  1. Laboratoire de Physiologie Animale, Institut de Biologie et Médecine Moléculaire, Université Libre de Bruxelles, 12 rue des Professeur Jeneer et Brachet, Gosselies, 6041, Belgium

    Frédéric Van Gool, Mara Gallí & Oberdan Leo

  2. Laboratoire de Chimie Biologique, Institut de Biologie et Médecine Moléculaire, Université Libre de Bruxelles, 12 rue des Professeur Jeneer et Brachet, Gosselies, 6041, Belgium

    Cyril Gueydan & Véronique Kruys

  3. Laboratory for Molecular Biology of Ectoparasites, Institut de Biologie et Médecine Moléculaire, Université Libre de Bruxelles, 12 rue des Professeur Jeneer et Brachet, Gosselies, 6041, Belgium

    Pierre-Paul Prevot

  4. Clinical Research Division, Fred Hutchinson Cancer Research Center, D2-100, 1100 Fairview Avenue North, Seattle, 98109, Washington, USA

    Antonio Bedalov

  5. The Center for Blood Research and Department of Genetics, Howard Hughes Medical Institute, The Children's Hospital, Harvard University Medical School, 300 Longwood Avenue, Boston, 02115, Massachusetts, USA

    Raul Mostoslavsky & Frederick W Alt

  6. TopoTarget Switzerland S.A., Avenue de Sévelin 18-20, Lausanne, CH-1004, Switzerland

    Thibaut De Smedt

Authors
  1. Frédéric Van Gool
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  10. Oberdan Leo
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Contributions

F.V.G. and M.G. generated all of the in vitro data presented in the manuscript. V.K. and C.G. designed and provided assistance for the polysome purification and the northern blot experiments and helped with the analysis of the data. P.-P.P. and F.V.G. designed and performed the in vivo experiments. A.B. and T.D.S. provided the pharmacological reagents used in this study (cambinol and APO866, respectively). R.M. and F.W.A. provided bone marrow cells from Sirt6-knockout mice. F.V.G. and O.L. designed the study and analyzed the data. O.L. directed the project and wrote the manuscript.

Corresponding author

Correspondence to Oberdan Leo.

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Competing interests

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.

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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

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