The role of indoleamine 2,3-dioxygenase (IDO) in the pathophysiology of interferon-alpha-induced depression

Abstract

The mechanisms by which administration of interferon-alpha induces neuropsychiatric side effects, such as depressive symptoms and changes in cognitive function, are not clear as yet. Direct influence on serotonergic neurotransmission may contribute to these side effects. In addition, the enzyme indoleamine 2,3-dioxygenase (IDO), which converts tryptophan into kynurenine, may play an important role, first, because IDO activation leads to reduced levels of tryptophan, the precursor of serotonin (5-HT), and thus to reduced central 5-HT synthesis. Second, kynurenine metabolites such as 3-hydroxy-kynurenine (3-OH-KYN) and quinolinic acid (QUIN) have toxic effects on brain function. 3-OH-KYN is able to produce oxidative stress by increasing the production of reactive oxygen species (ROS), and QUIN may produce overstimulation of hippocampal N-methyl-D-aspartate (NMDA) receptors, which leads to apoptosis and hippocampal atrophy. Both ROS overproduction and hippocampal atrophy caused by NMDA overstimulation have been associated with depression.

Fig. 1: The role of indoleamine 2,3-dioxygenase (IDO) in cytokine-induced lowered tryptophan (TRP) levels and production of neurotoxic metabolites. The dotted arrows indicate that IL-4 and IL-10 diminish IDO activity. The diagonal arrows leading from IFN-α and TNF-α to IDO indicate that these cytokines increase IDO activity and, thus, cause increased metabolism of TRP, resulting in decreased availability of TRP that crosses the BBB to synthesize 5-HT. The horizontal arrows between IFN-α and IFN-γ and between TNF-α and IFN-γ refer to the fact that IFN-α and TNF-α increase production of IFN-γ, which exerts a powerful stimulating effect (thick vertical arrow) on IDO activity. NMDA = N-methyl-D-aspartate, QUIN = quinolinic acid, 3-OH-KYN =3-hydroxy-kynurenine, 5-HT = serotonin, KYN = kynurenine, KYNA = kynurenate, BBB = blood–brain barrier, IL-4 = interleukin-4, IFN-α = interferon-α, TNF-α = tumour necrosis factor-α.