Limits...
Immunological Relevance of the Coevolution of IDO1 and AHR.

Jaronen M, Quintana FJ - Front Immunol (2014)

Bottom Line: Indoleamine-2,3-dioxygenase (IDO) and tryptophan-2,3-dioxygenase (TDO) are considered rate-limiting enzymes in the tryptophan catabolism and play important roles in the regulation of the immunity.Moreover, AHR and IDO/TDO are closely interconnected: AHR regulates IDO and TDO expression, and kynurenine produced by IDO/TDO is an AHR agonist.In this review, we propose to examine the relationship between AHR and IDO/TDO and its relevance for the regulation of the immune response in health and disease.

View Article: PubMed Central - PubMed

Affiliation: Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School , Boston, MA , USA.

ABSTRACT
The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor initially identified because of its role in controlling the cellular response to environmental molecules. More recently, AHR has been shown to play a crucial role in controlling innate and adaptive immune responses through several mechanisms, one of which is the regulation of tryptophan metabolism. Indoleamine-2,3-dioxygenase (IDO) and tryptophan-2,3-dioxygenase (TDO) are considered rate-limiting enzymes in the tryptophan catabolism and play important roles in the regulation of the immunity. Moreover, AHR and IDO/TDO are closely interconnected: AHR regulates IDO and TDO expression, and kynurenine produced by IDO/TDO is an AHR agonist. In this review, we propose to examine the relationship between AHR and IDO/TDO and its relevance for the regulation of the immune response in health and disease.

No MeSH data available.


Interplay between tryptophan metabolism and AHR. Tryptophan is metabolized by TDO2 and IDO1 to l-kynurenine, which is further converted to kynurenic acid. Both l-kynurenine and kynurenic acid can activate AHR. In addition, AHR activity is influenced by environment and therapy. Finally, AHR can activate either genomic or non-genomic AHR-dependent signaling pathways. Red arrows indicate tryptophan catabolism pathways, blue arrows indicate AHR activation, and black arrows indicate pathways activated by AHR.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4202789&req=5

Figure 1: Interplay between tryptophan metabolism and AHR. Tryptophan is metabolized by TDO2 and IDO1 to l-kynurenine, which is further converted to kynurenic acid. Both l-kynurenine and kynurenic acid can activate AHR. In addition, AHR activity is influenced by environment and therapy. Finally, AHR can activate either genomic or non-genomic AHR-dependent signaling pathways. Red arrows indicate tryptophan catabolism pathways, blue arrows indicate AHR activation, and black arrows indicate pathways activated by AHR.

Mentions: Tryptophan metabolites have become one of the most interesting groups of endogenous AHR ligands. Especially kynurenine, an immediate tryptophan metabolite, has been extensively studied in recent years. The metabolic fate of tryptophan is conversion into a range of neuroactive substances, such as serotonin and melatonin. In addition, tryptophan can be catabolized into kynurenine metabolites. Indoleamine-2,3-dioxygenase (IDO1), tryptophan-2,3-dioxygenase (TDO), and recently discovered IDO-related enzyme IDO2 (54) are the first and rate-limiting enzymes converting tryptophan to N-formylkynurenine (55, 56) which is then metabolized to l-kynurenine. Both TDO and IDO1 are thought to be intracellular enzymes (57, 58). Therefore, ATP-binding cassette (ABC) transporter (59), enzyme facilitating cellular entry of tryptophan, is considered to be another rate-limiting factor in tryptophan catabolism (60). l-Kynurenine can be catabolized by three different ways: (1) kynurenine monooxygenase, kynureninase, and 3-hydroxyanthranilic acid oxidase catalyze the synthesis of anthranilic acid, 3-hydroxyanthranilic acid, quinolinic acid, and 3-hydroxykynurenine. (2) Kynurenine aminotransfereases catalyze the synthesis of kynurenic acid. (3) Kynurenine monooxygenase and kynurenine aminotransfereases catalyze the synthesis of xanthurenic acid (Figure 1) [reviewed in Ref. (61)].


Immunological Relevance of the Coevolution of IDO1 and AHR.

Jaronen M, Quintana FJ - Front Immunol (2014)

Interplay between tryptophan metabolism and AHR. Tryptophan is metabolized by TDO2 and IDO1 to l-kynurenine, which is further converted to kynurenic acid. Both l-kynurenine and kynurenic acid can activate AHR. In addition, AHR activity is influenced by environment and therapy. Finally, AHR can activate either genomic or non-genomic AHR-dependent signaling pathways. Red arrows indicate tryptophan catabolism pathways, blue arrows indicate AHR activation, and black arrows indicate pathways activated by AHR.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4202789&req=5

Figure 1: Interplay between tryptophan metabolism and AHR. Tryptophan is metabolized by TDO2 and IDO1 to l-kynurenine, which is further converted to kynurenic acid. Both l-kynurenine and kynurenic acid can activate AHR. In addition, AHR activity is influenced by environment and therapy. Finally, AHR can activate either genomic or non-genomic AHR-dependent signaling pathways. Red arrows indicate tryptophan catabolism pathways, blue arrows indicate AHR activation, and black arrows indicate pathways activated by AHR.
Mentions: Tryptophan metabolites have become one of the most interesting groups of endogenous AHR ligands. Especially kynurenine, an immediate tryptophan metabolite, has been extensively studied in recent years. The metabolic fate of tryptophan is conversion into a range of neuroactive substances, such as serotonin and melatonin. In addition, tryptophan can be catabolized into kynurenine metabolites. Indoleamine-2,3-dioxygenase (IDO1), tryptophan-2,3-dioxygenase (TDO), and recently discovered IDO-related enzyme IDO2 (54) are the first and rate-limiting enzymes converting tryptophan to N-formylkynurenine (55, 56) which is then metabolized to l-kynurenine. Both TDO and IDO1 are thought to be intracellular enzymes (57, 58). Therefore, ATP-binding cassette (ABC) transporter (59), enzyme facilitating cellular entry of tryptophan, is considered to be another rate-limiting factor in tryptophan catabolism (60). l-Kynurenine can be catabolized by three different ways: (1) kynurenine monooxygenase, kynureninase, and 3-hydroxyanthranilic acid oxidase catalyze the synthesis of anthranilic acid, 3-hydroxyanthranilic acid, quinolinic acid, and 3-hydroxykynurenine. (2) Kynurenine aminotransfereases catalyze the synthesis of kynurenic acid. (3) Kynurenine monooxygenase and kynurenine aminotransfereases catalyze the synthesis of xanthurenic acid (Figure 1) [reviewed in Ref. (61)].

Bottom Line: Indoleamine-2,3-dioxygenase (IDO) and tryptophan-2,3-dioxygenase (TDO) are considered rate-limiting enzymes in the tryptophan catabolism and play important roles in the regulation of the immunity.Moreover, AHR and IDO/TDO are closely interconnected: AHR regulates IDO and TDO expression, and kynurenine produced by IDO/TDO is an AHR agonist.In this review, we propose to examine the relationship between AHR and IDO/TDO and its relevance for the regulation of the immune response in health and disease.

View Article: PubMed Central - PubMed

Affiliation: Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School , Boston, MA , USA.

ABSTRACT
The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor initially identified because of its role in controlling the cellular response to environmental molecules. More recently, AHR has been shown to play a crucial role in controlling innate and adaptive immune responses through several mechanisms, one of which is the regulation of tryptophan metabolism. Indoleamine-2,3-dioxygenase (IDO) and tryptophan-2,3-dioxygenase (TDO) are considered rate-limiting enzymes in the tryptophan catabolism and play important roles in the regulation of the immunity. Moreover, AHR and IDO/TDO are closely interconnected: AHR regulates IDO and TDO expression, and kynurenine produced by IDO/TDO is an AHR agonist. In this review, we propose to examine the relationship between AHR and IDO/TDO and its relevance for the regulation of the immune response in health and disease.

No MeSH data available.