Indoleamine 2,3‐Dioxygenase: Transcriptional Regulation and Autoimmunity

Abstract

Indoleamine 2,3-dioxygenase (IDO) is a haem-containing enzyme that catalyses the oxidative cleavage of the indole ring in L-tryptophan (L-Trp), regulating this amino acid catabolism at the initial, rate-limiting level in a specific pathway. L-Trp, the least abundant of the essential amino acids, is utilized for protein synthesis and as a precursor of the neurotransmitter serotonin, yet the majority of the dietary intake is degraded along the so-called kynurenine pathway (named after the first metabolite, L-kynurenine), eventually leading to the biosynthesis of NAD þ . However, the same metabolic pathway, with initial formation of L-kynurenine, can be activated by two distinct, poorly homologous (12%) enzymes: IDO and tryptophan 2,3-dioxygenase (TDO).TDO is a constitutive enzyme restricted to the liver, whereas IDO is an inducible, intracellular enzyme widely expressed in several organs, and in particular in the lung, small and large intestine, spleen, kidney, stomach, brain and placenta. Remarkable expression of IDO is found in myeloid lineage cells (dendritic cells (DCs), monocytes, macrophages, eosinophils), epithelial cells, fibroblasts, vascular smooth muscle and endothelial cells, and in certain tumours as well. The two enzymes differ in substrate specificity. TDO is highly specific for the L-isomer of Trp, whereas IDO is capable of oxidizing a broad range of substrates, including not only L-Trp, but also D-Trp,