TNF regulates cellular NAD+ metabolism in primary macrophages.
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 on 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 up-regulation 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.
Iqbal
Jameel
J
Department of Endocrinology and Mount Sinai Bone Program, Mount Sinai School of Medicine, New York, NY 10029, USA.
Zaidi
Mone
M
D000818:Animals; D002478:Cells, Cultured; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D009097:Multienzyme Complexes / Q000378:metabolism; D009243:NAD / Q000378:metabolism*; D010084:Oxidation-Reduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage*
D009097:Multienzyme Complexes; D014409:Tumor Necrosis Factor-alpha; D009243:NAD