Interferon-γ-Induced Conversion of Tryptophan: Immunologic and Neuropsychiatric Aspects

Abstract

Tryptophan is an essential amino acid and the least abundant constituent of proteins. In parallel it represents a source for two important biochemical pathways: the generation of neurotransmitter 5-hydroxytryptamine (serotonin) by the tetrahydrobiopterin-dependent tryptophan 5-hydroxylase, and the formation of kynurenine derivatives and nicotinamide adenine dinucleotides initiated by the enzymes tryptophan pyrrolase (tryptophan 2,3-dioxygenase, TDO) and indoleamine 2,3-dioxygenase (IDO). Whereas TDO is located in the liver cells, IDO is expressed in a large variety of cells and is inducible by the cytokine interferon-gamma. Therefore, accelerated tryptophan degradation is observed in diseases and disorders concomitant with cellular immune activation, e. g. infectious, autoimmune, and malignant diseases, as well as during pregnancy. According to the cytostatic and antiproliferative properties of tryptophan-depletion on T lymphocytes, activated T-helper type 1 (Th-1) cells may down-regulate immune response via degradation of tryptophan. Especially in states of persistent immune activation availability of free serum tryptophan is diminished and as a consequence of reduced serotonin production, serotonergic functions may as well be affected. Accumulation of neuroactive kynurenine metabolites such as quinolinic acid may contribute to the development of neurologic/psychiatric disorders. Thus, IDO seems to represent a link between the immunological network and neuroendocrine functions with far reaching consequences in regard to the psychological status of patients. These observations provide a basis for the better understanding of mood disorder and related symptoms in chronic diseases.

Inoculation of Bacillus Calmette-Guerin to mice induces an acute episode of sickness behavior followed by chronic depressive-like behavior

“…This measure provides therefore an accurate indication of the entire systemic peripheral cytokine response to ip BCG inoculation. On the other hand, although IDO is present in most extrahepatic tissues (Wirleitner et al, 2003), lungs have been chosen as preferential peripheral target tissue to control the efficiency of the response to BCG on the basis of their ability to show a huge and sustained increase of IDO in these conditions (Moreau et al, 2005) and as the main site of mycobacteria development (Costello and Izumi, 1971).…”

“…Since KYN is the major product of TRP degradation (Dale et al, 2000), these results can be explained by an enhanced activation of the TRP-catabolizing enzyme indoleamine 2,3-dioxygenase (IDO) (Wirleitner et al, 2003). This extrahepatic enzyme is activated in monocytes, macrophages and brain microglia in response to proinflammatory cytokines, mainly interferon-gamma (IFN-γ) and tumor necrosis factoralpha (TNF-α) (Fujigaki et al, 2006;Takikawa et al, 1999).…”

Immune Dysfunction in Autism: A Pathway to Treatment

“…100 The enzymes responsible for this conversion are under the control of cytokines such as IFN␥ and IL-1. 101,102 Thus, increased tryptophan degradation as a result of aberrant immune activation could affect serotonin levels and thus affect behavior.…”

IDO and interferon-α-induced depressive symptoms: a shift in hypothesis from tryptophan depletion to neurotoxicity

“…[11][12][13][14] The enzyme indoleamine 2,3-dioxygenase (IDO) constitutes a link between the 5-HT system and immune activation. 15 This enzyme is located in nonhepatic organs throughout the body and is also present in monocytes, macrophages and microglial cells within the brain parenchyma. 16 IDO activity is mainly induced by the proinflammatory cytokine IFN-g and converts TRP into kynurenine (KYN), which, in the case of overstimulation, may lead to lowered TRP concentrations.…”

“…16 IDO activity is mainly induced by the proinflammatory cytokine IFN-g and converts TRP into kynurenine (KYN), which, in the case of overstimulation, may lead to lowered TRP concentrations. 15,17 KYN is further metabolized into a series of compounds (see Figure 1), some with neurotoxic properties. 3-Hydroxykynurenine (3-OH-KYN) leads to the production of reactive oxygen species that initiate neuronal apoptosis.…”