Intracellular NAD levels regulate tumor necrosis factor protein synthesis in a sirtuin-dependent manner.
Intracellular NAD levels regulate tumor necrosis factor protein synthesis in a sirtuin-dependent manner.
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Uncontrolled TNF-α synthesis is known to play an important role in numerous inflammatory disorders, and multiple transcriptional and post-transcriptional regulatory mechanisms have therefore evolved to dampen the production of this important pro-inflammatory cytokine. By examining the anti-inflammatory properties of the vitamin B3 constituent nicotinamide, we have uncovered a novel regulatory pathway controlling TNF-α production. Exogenous nicotinamide inhibits TNF-α secretion through modulation of mRNA translation efficiency. Moreover, the capacity to produce TNF-α appears to be directly correlated with intracellular NAD levels, suggesting that a NAD-dependent biological event that can be inhibited by nicotinamide controls TNF-α synthesis in cells of the immune system. Sirtuins represent NAD-dependent deacetylases involved in regulation of gene expression in both mammals and yeasts, and are known to be inhibited by nicotinamide. We demonstrate herein that similarly to nicotinamide, structurally unrelated sirtuin inhibitors downregulate TNF-α secretion with minimal effect on TNF-α gene transcription. By over-expressing individual sirtuin members in cell lines transiently expressing TNF-α, we have identified SIRT6 as a sirtuin member able to upregulate TNF-α synthesis in vitro. In agreement with this finding, bone-marrow derived dendritic cells from SIRT6 KO mice display reduced TNF-α synthesis in response to CpG. Collectively, these data delineate a novel relationship between metabolism and the inflammatory response, by uncovering the role of SIRT6 in the control of TNF-α secretion.
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DOI：
10.1164/rccm.200404-563oc
发表时间：
2005-02-15
影响因子：
24.7
作者：
Ye, SQ;Simon, BA;Garcia, JGN
通讯作者：
Garcia, JGN
影响因子：
4.4
作者：
Fukuzawa, M;Satoh, J;Toyota, T
通讯作者：
Toyota, T
影响因子：
64.5
作者：
Mostoslavsky, R;Chua, KF;Alt, FW
通讯作者：
Alt, FW
DOI：
10.1073/pnas.192222999
发表时间：
2002-09-17
影响因子：
11.1
作者：
Ulloa, L;Ochani, M;Tracey, KJ
通讯作者：
Tracey, KJ
影响因子：
11.2
作者：
Heltweg, B;Gatbonton, T;Bedalov, A
通讯作者：
Bedalov, A