Intracellular NAD levels regulate tumor necrosis factor protein synthesis in a sirtuin-dependent manner
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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.
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In macrophages, blocking NAMPT and lowering NAD+ reduced secretion of proinflammatory cytokines such as TNF and produced morphological changes including less spreading.
“inhibition of NAMPT and subsequent depletion of NAD+ pools in macrophages decreased the secretion of proinflammatory cytokines, such as TNF, and caused morphological changes, such as reduced spreading in these cells100,101”
From NAD+ metabolism and its roles in cellular processes during ageing (2021) · cites this paper as [100]
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- Authors
- Van Gool, F., Gallí, M., Gueydan, C., Kruys, V., Prevot, P.-P., Bedalov, A., Mostoslavsky, R., Alt, F. W., De Smedt, T., & Leo, O.
- Affiliations
- Université Libre de Bruxelles (BE)
- Fred Hutch Cancer Center (US)
- Howard Hughes Medical Institute (US)
- Venue
- Nature Medicine
- Published
- 2009-01-18
- Volume
- 15
- Issue
- 2
- Pages
- 206-210
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC2845476
- OpenAlex
- W2008776460
- Cited by
- 285
- References
- 58
- Citations by year
- 2026: 4 · 2025: 12 · 2024: 3 · 2023: 12 · 2022: 12 · 2021: 19 · 2020: 22 · 2019: 17 · 2018: 18 · 2017: 20 · 2016: 17 · 2015: 21 · 2014: 13 · 2013: 26 · 2012: 20
- FWCI
- 15.86
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- authors@Fred Hutch (Fred Hutchinson Cancer Research Center) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Dépôt institutionnel de l'Université libre de Bruxelles (Université Libre de Bruxelles) (submittedVersion)
- Funders
- National Cancer Institute (R01CA129132)
- Topics
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- TNF-α, SIRT6, NAD+ metabolism, visfatin, sepsis, post-transcriptional regulation, mRNA translation, inflammation, immune cells, NAD biosynthesis, immunometabolism
- MeSH terms
- Animals, Enzyme-Linked Immunosorbent Assay, NAD, Tumor Necrosis Factor-alpha, Reverse Transcriptase Polymerase Chain Reaction, Mice, Nicotinamide Phosphoribosyltransferase
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