TNF regulates cellular NAD+ metabolism in primary macrophages
TNF regulates cellular NAD+ metabolism in primary macrophages
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DOI：
10.1016/j.bbrc.2006.02.109
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发表时间：
2006-04-21
影响因子：
3.1
通讯作者：
Zaidi, M
中科院分区：
文献类型：
--
作者：
Iqbal, J;Zaidi, M
已知炎性细胞因子TNF影响葡萄糖和脂质代谢，其中其作用导致恶病质状态。尽管TNF与代谢之间的联系已得到充分证实，但TNF与NAD（+）代谢之间的关系仍不清楚。在本报告中，我们评估了TNF油NAD（+）代谢在TNF的主要自分泌靶细胞-巨噬细胞中的作用。我们设计了针对所有NAD（+）代谢酶的实时PCR引物，用于检测TNF诱导的随时间的变化。我们发现，TNF矛盾地上调了用于增加NAD（+）水平的酶，如IDO和PBEF，以及降低NAD（+）水平的酶，如CD 38和CD 157。通过检测细胞NAD（+）水平中TNF介导的变化来评估这些mRNA变化的意义。用TNF处理巨噬细胞随时间降低NAD（+）水平，表明NAD（+）降解酶的增加占主导地位。为了评估是否是这种情况，我们在CD 38基因缺失的动物中测量了TNF介导的NAD（+）水平的变化。在CD 38-/-巨噬细胞中，TNF的作用被逆转，随着时间的推移，TNF增加NAD（+）水平。我们的发现有三方面的意义：（1）我们证实TNF通过调节主要NAD（+）代谢酶的表达来影响NAD（+）代谢，（2）TNF诱导的细胞NAD（+）水平的降低是通过细胞外酶的上调来实现的，（3）我们为观察到的肿瘤坏死因子依赖性疾病与组织中NAD（+）含量减少的临床联系提供了一种机制。(c)2006年爱思唯尔公司All rights reserved.
The inflammatory cytokine TNF is known to affect glucose and lipid metabolism, where its action leads to a cachexic state. Despite a well-established connection of TNF to metabolism, the relationship between TNF and NAD(+) metabolism remains unclear. In this report, we evaluated the effects of TNF oil NAD(+) metabolism in cells that are TNF's primary autocrine target-macrophages. We designed real-time PCR primers to all NAD(+) metabolic enzymes, which we used to examine TNF-induced changes over time. We found that TNF paradoxically up-regulated enzymes that served to increase NAD(+) levels, such as IDO and PBEF, as well as enzymes that decrease NAD(+) levels, such as CD38 and CD157. The significance of these mRNA changes was evaluated by examining TNF-mediated changes in cellular NAD(+) levels. Treatment of macrophages with TNF decreased NAD(+) levels over time, suggesting that increases in NAD(+)-degrading enzymes were dominant. To evaluate whether this was the case, we measured TNF-mediated changes in NAD(+) levels in animals where CD38 was genetically deleted. In CD38-/- macrophages, the effects of TNF were reversed, with TNF increasing NAD(+) levels over time. The significance of our findings is threefold: (1) we establish that TNF affects NAD(+) metabolism by regulating the expression of major NAD(+) metabolic enzymes, (2) TNF-induced decreases in cellular NAD(+) levels were carried out through the upregulation of extracellularly situated enzymes, and (3) we provide a mechanism for the observed clinical connection of TNF-dependent diseases to tissue reductions in NAD(+) content. (c) 2006 Elsevier Inc. All rights reserved.