IDO induction in IFN-gamma activated astroglia: a role in improving cell viability during oxidative stress.
In the central nervous system (CNS), astrocytes play an integral role in the maintenance of neuronal viability and function. Inflammation within the CNS increases the concentration of oxidative metabolites and, therefore, the potential for NAD depletion through increased poly-(ADP-ribose) polymerase (PARP) activity. However, the activity of indoleamine 2,3-dioxygenase (IDO), the rate limiting enzyme for de novo NAD synthesis, is also markedly increased in astrocytes during inflammation. This study investigated the role of IDO induction in the maintenance of intracellular NAD and its relationship to improved cell viability under conditions of increased oxidative stress in the human astroglioma cell line, HTB-138. Treatment with the pro-inflammatory cytokine IFN-gamma increased IDO activity in these cells. Intracellular NAD levels also increased significantly after treatment with IFN-gamma in the presence of a PARP inhibitor. Pretreatment of astroglial cells with IFN-gamma significantly moderated both the drop in intracellular NAD concentration and cell death following exposure to hydrogen peroxide. These results suggest that induction of IDO and subsequent de novo NAD synthesis may contribute to the maintenance of intracellular NAD levels and cell viability under conditions of increased oxidative stress.
School of Physiology and Pharmacology, Faculty of Medicine, University of New Soulth Wales, Sydney, Australia.
R S
RS
Grant
H
H
Naif
M
M
Espinosa
V
V
Kapoor
D001253:Astrocytes / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D001254:Astrocytoma; D001549:Benzamides / Q000494:pharmacology; D002470:Cell Survival; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007371:Interferon-gamma / Q000494:pharmacology*; D009243:NAD / Q000378:metabolism; D018384:Oxidative Stress; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011994:Recombinant Proteins; D014364:Tryptophan / Q000031:analogs & derivatives / Q000494:pharmacology; D014366:Tryptophan Oxygenase / Q000096:biosynthesis*; D014407:Tumor Cells, Cultured
D001549:Benzamides; D004791:Enzyme Inhibitors; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011994:Recombinant Proteins; D009243:NAD; C026380:6-chlorotryptophan; D007371:Interferon-gamma; D014364:Tryptophan; C025160:3-aminobenzamide; D006861:Hydrogen Peroxide; D014366:Tryptophan Oxygenase