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Indoleamine 2, 3-Dioxygenase Regulation of Immune Response (Review)

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Indoleamine 2, 3-Dioxygenase Regulation of Immune Response (Review) MOLECULAR MEDICINE REPORTS 17: 4867-4873, 2018 Indoleamine 2, 3-dioxygenase regulation of immune response (Review) HAO WU1, JIANPING GONG1 and YONG LIU2 1Chongqing Key Laboratory of Hepatobiliary Surgery and Department of Hepatobiliary Surgery, Second Affiliated Hospital, Chongqing Medical University, Chongqing 400010; 2Department of Hepatobiliary Surgery, The People's Hospital of Hechuan, Chongqing 401520, P.R. China Received November 28, 2016; Accepted January 4, 2018 DOI: 10.3892/mmr.2018.8537 Abstract. Indoleamine 2, 3-dioxygenase (IDO) catalyzes Contents the initial and rate-limiting step in the degradation pathway of the essential amino acid tryptophan and is expressed by 1. Introduction professional antigen presenting cells (APCs), epithelial cells, 2. Properties of the IDO enzyme vascular endothelium and tumor cells. IDO-mediated cata- 3. IDO pathways and immune regulation bolic products, which are additionally termed ʻkynureninesʼ, 4. Role of IDO in immune suppression exerts important immunosuppressive functions primarily via 5. Strategies to target IDO regulating T effector cell anergy and inducing the proliferation 6. Conclusions of T regulatory cells. This endogenous tolerogenic pathway has a critical effect on mediating the magnitude of immune responses under various stress conditions, including tumor, 1. Introduction infection and transplantation. The present review evaluates the recent progress in elucidating how catabolism of tryptophan As a highly evolved biological response, immunoregulation not regulated by IDO modulates the immune response to inflam- only coordinates inflammation and innate immunity, however matory and immunological signals. Blocking this pathway may may additionally modulate adaptive immunity and establish be a novel adjuvant therapeutic strategy for clinical application self-tolerance. Continuous access to nutrients is a primary in immunotherapy. requirement for cell proliferation, and controlling nutrient supply is an ancient survival strategy that may additionally regulate immune response. Indoleaine 2,3-dioxygenase (IDO) is a tryptophan enzyme composed of two-helical α-domains with a heme group located between them (1-2). A total of two forms of the IDO gene (IDO1 and IDO2) have been identified, however, the majority of studies have investigated the function of IDO1, and the physiological role of IDO2 remains unclear. Correspondence to: Dr Yong Liu, Department of Hepatobiliary The immune regulating properties of IDO were first Surgery, The People's Hospital of Hechuan, 1366 Xieran Avenue, Chongqing 401520, P.R. China described in the prevention of T-cell-mediated allogenetic E-mail: [email protected] fetus rejection in mice, verifying that IDO synthesized in placental cells protects the mammalian fetus from maternal Abbreviations: IDO, Indoleamine 2, 3‑dioxygenase; APCs, T lymphocyte attack (3). The degradation of tryptophan and antigen presenting cells; STAT1, activated signal transducer and accumulation of tryptophan-derived catabolites by IDO may activator of transcription 1; NF‑κB, nuclear factor‑kappa B; iNOS, lead to the suppression of T-cell proliferation at mid-G1 phase, inducible nitric oxide synthase; mTOR, mammalian target of the inhibition of activated T effector cells, and the induction Rapamycin; GCN2, general control nondepressible‑2; AhR, aryl of T, B, and natural killer cell apoptosis (1,3). IDO has previ- hydrocarbon receptor; DCs, dendritic cells; eIF‑2α, eukaryotic ously been demonstrated to be expressed in various tissues, translation initiation factor 2 α; PKC‑θ, protein kinase C‑sita; ILT3, including human lung, placenta, and small intestine and is Ig‑like transcript 3; Tat, N‑terminal domain of human immune upregulated during inflammation. Physiologically, IDO is deficiency virus‑1 transactivator regulatory protein; JAKs, janus activated kinases; PI3K, phosphatidyl inositol 3‑kinase; 1‑MT, pivotal in regulating the immune response to antigenic chal- 1‑methyl‑DL‑tryptophan; BIN‑1, bridging integrator 1 lenges at mucosal surfaces in the digestive tract and lungs (4). Furthermore, the induction of IDO and the subsequent Key words: indoleamine 2, 3-dioxygenase, immune regulation, deprivation of tryptophan in the microenvironment, exerts an regulatory T cell, tryptophan, kynurenine antiproliferative effect on T cells and infectious pathogens (3). IDO is recognized to be an authentic regulator of immunity in a variety of pathophysiological settings, including infections, 4868 WU et al: INDOLEAMINE 2, 3-DIOXYGENASE REGULATION OF IMMUNE RESPONSE transplantation and cancer (1,5). The present review aimed appears to be pivotal in imposing restrictions on potentially to evaluate recent progress and evidence regarding how IDO exaggerated inflammatory reactions to danger signals. IDO activity impacts the immune responses to inflammatory and contributes to immune regulation via catalyzing tryptophan immunological signals. along the kynurenine pathway. IDO modifies the immune response via three pathways: i) by depleting tryptophan in 2. Properties of the IDO enzyme the local microenvironment, IDO results in metabolic stress sensed by general control nondepressible‑2 (GCN2) kinase IDO, a 407-amino acid heme-containing cytoplasmic protein, and mammalian target of Rapamycin (mTOR), which even- is coded by the INDO gene located on chromosome 8p12 in tually promotes anergy in responding T cells and directs the humans. The enzyme is responsible for the primary mecha- conversion of regulatory T cells (Treg) (11); ii) by producing nism of extra-hepatic tryptophan metabolism and is expressed tryptophan catabolism that binds to a natural ligand for the aryl in professional APCs, epithelial cells, vascular endothe- hydrocarbon receptor (AhR), IDO similarly results in immu- lium and tumor cells (1,2,5). The IDO gene is regulated by nosuppressive effects on the immunogenicity of dendritic cell upstream interferon (IFN)-γ responsive elements that bind (DCs) reduction and the Treg conversion (12); iii) by inducing to activated signal transducer and activator of transcription 1 Treg function, IDO as a signaling protein shapes the immu- (STAT1), interferon regulatory factor-1 and nuclear factor-κB nological microenviroment in vivo. The following section (NF-κB) (6). IDO activity is strongly associated with an identifies mechanisms by which IDO pathways are implicated environment enriched with redox active compounds, which in modulating immune regulation. are required to generate the active Fe2+ form for tryptophan metabolism. IDO enzymatically degrades tryptophan and IDO depletes tryptophan and produces bioactive downstream other indoleamine compounds via oxidative cleavage of the metabolites pyrrole ring, resulting in an accumulation of downstream Effector pathways: GCN2 activation and mTOR suppression. breakdown products of kynurenine, in addition to other IDO activity decreases the local concentration of tryptophan defined metabolic products, which have been previously in the IDO-expressing cell and in the microenvironment reported to exhibit biological activity in the immune system surrounding nearby cells. Tryptophan depletion by IDO may (Fig. 1) (7). Currently, the ratio of kynurenine/tryptophan is act as a potential regulatory signal via two signaling pathways: regarded as a method to determine the enzymatic activity of activation of the molecular stress-response pathway, including IDO. Furthermore, adding strong reductants (methylenum GCN2 kinase, which directly binds to uncharged trypto- coeruleum, vitamin C) into the IDO culture system results phan tRNAs, and suppression of the mTOR kinase pathway, in the maintenance of the superoxide anion, an accessory which is known to regulate immune reactions (13). DCs factor of IDO, at a high concentration, thus enhancing its expressing IDO may induce the immunosuppressive activity activity. The enzymatic activity of IDO is mitigated by natural of Tregs, however this effect is observed to be abrogated by immunomodulators including nitric oxide, which are able to genetic disruption of GCN2. Depletion of tryptophan has combine with the heme tetrapyrrole group (8). been demonstrated to mediate the activation of the GCN2 IDO expression has been revealed to be markedly different pathway for downregulating the CD3 ζ-chain in CD8+ T between various cells depending on the specific cell type, the cells and blocking Th17 cell differentiation (14). GCN2 maturational state and the activation status of the cells. The cata- blunts protein translation by phosphorylating its downstream bolic pathway regulated by IDO activity results from activity of target, initiating eukaryotic translation initiation factor 2 α two different genes, termed IDO1 and IDO2. Mice and humans (eIF-2α), resulting in blockade readout of the majority of RNA possess the two associated genes tightly in a syntenic region of transcripts, except for the LIP RNA transcript. IDO supports chromosome 8 (9). The two genes exhibit sequence homology, interleukin (IL)‑6 production through GCN2 activation and however, they respond differently to various signals in distinct was revealed to affect myeloid-derived suppressor cell func- cell types, and their patterns of gene regulation and expression tion and tumor progression (15). A previous study in nephritis are not identical. Currently, IDO1 is the more comprehensively mouse models, conducted by Chaudhary et al (16), suggested studied of the two genes, however IDO2 is gradually being recog- that kidney injury of mice were improved by amino
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