Indoleamine 2,3-Dioxygenase Activity Increases NAD+ Production in IFN-γ-Stimulated Human Primary Mononuclear Cells

Ross S Grant

doi:10.1177/1178646917751636

Indoleamine 2,3-Dioxygenase Activity Increases NAD+ Production in IFN-γ-Stimulated Human Primary Mononuclear Cells

Int J Tryptophan Res. 2018 Jan 8:11:1178646917751636. doi: 10.1177/1178646917751636. eCollection 2018.

Author

Ross S Grant^{1

2

3}

Affiliations

¹ Faculty of Medicine, School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia.
² Australasian Research Institute, Sydney Adventist Hospital, Sydney, NSW, Australia.
³ Sydney Adventist Hospital Clinical School, University of Sydney, Sydney, NSW, Australia.

Abstract

IFN-γ activation of mononuclear phagocytes significantly increases indoleamine 2,3-dioxygenase (IDO) and flux through the kynurenine pathway (KP). However, the effect of IDO on NAD+ synthesis, the end product of KP metabolism, is unknown. To investigate this, primary human peripheral blood mononuclear cells were cultured up to 10 days and activated with IFN-γ in the presence or absence of a poly(ADP-ribose) polymerase (PARP) inhibitor. Day 10 macrophages had significantly higher NAD+ levels compared with monocytes. IFN-γ activation of macrophages resulted in the highest induction of IDO but decreased intracellular NAD+ concentrations at both 24 and 48 hours. However, IFN-γ activation of both day 6 and day 10 macrophages in the presence of a PARP inhibitor resulted in significantly higher intracellular NAD+ levels at 24 hours. This study provides evidence for the first time that an immune-mediated increase in IDO activity increases NAD+ biosynthesis concomitantly with an increase in NAD+ catabolism in primary human macrophages.

Keywords: NAD+; PARP; indoleamine 2,3-dioxygenase; macrophage; monocyte; tryptophan.