Disease relevance of INDO

• The growth of Chlamydia psittaci was strongly inhibited in INDO +ve cells but not in INDO -ve cells after treatment with Cd2+ or Zn2+ [1].
• To study the role of tryptophan degradation by indoleamine 2, 3-dioxygenase (INDO) in the control of Trypanosoma cruzi or Toxoplasma gondii replication, we used human fibroblasts and a fibrosarcoma cell line (2C4) [2].
• In our study, the effects of TNF-alpha, inhibitors of arachidonic acid (AA) metabolism (baicalein, BA; indomethacin, INDO; niflumic acid, NA; nordihydroguaiaretic acid, NDGA), and/or their combinations on undifferentiated or sodium butyrate (NaBt)-differentiated human colon adenocarcinoma HT-29 cells were compared [3].
• Inhibition of human herpes simplex virus type 2 by interferon gamma and tumor necrosis factor alpha is mediated by indoleamine 2,3-dioxygenase [4].
• We therefore conclude that the antiviral effect against HSV-2 mediated by type II interferon and TNF-alpha are dependent on IDO activation [4].

Psychiatry related information on INDO

• We propose that IDO is induced chronically by HIV infection, is further increased by opportunistic infections, and that this chronic loss of Trp initiates mechanisms responsible for the cachexia, dementia, diarrhea and possibly immunosuppression of AIDS patients [5].
• Indo-west Pacific fiddler crabs have simpler reproductive social behavior and are more marine and were thought to be ancestral to the more behaviorally complex and more terrestrial American species [6].
• IDO and interferon-alpha-induced depressive symptoms: a shift in hypothesis from tryptophan depletion to neurotoxicity [7].
• Low serum tryptophan levels, reduced macrophage IDO activity and high frequency of psychopathology in HCV patients [8].
• Indoleamine 2,3 dioxygenase and quinolinic acid immunoreactivity in Alzheimer's disease hippocampus [9].

High impact information on INDO

• The development of the syndrome may result from a confluence of several factors, including the ingestion of tryptophan, exposure to agents that activate indoleamine-2,3-dioxygenase, and possibly, impaired function of the hypothalamic-pituitary-adrenal axis [10].
• Plasma levels of L-kynurenine and quinolinic acid, which are metabolites of tryptophan, were significantly higher in four patients with active disease than in three patients studied after eosinophilia had resolved or in five normal subjects (P less than 0.001)--findings consistent with the activation of the enzyme indoleamine-2,3-dioxygenase [10].
• Degradation of tryptophan, an essential amino acid required for cell proliferation, was reported to be the mechanism of IDO-induced T cell suppression [11].
• Kynurenine, 3-hydroxykynurenine, and 3-hydroxyanthranilic acid, but no other IDO-induced tryptophan metabolites, suppressed the T cell response, the suppressive effects being additive [11].
• Inhibition of allogeneic T cell proliferation by indoleamine 2,3-dioxygenase-expressing dendritic cells: mediation of suppression by tryptophan metabolites [11].

Chemical compound and disease context of INDO

• Interestingly, use of TNFalpha, lipopolysaccharide, or Staphylococcus aureus Cowan I strain (SAC) alone does not induce IDO [12].
• CONCLUSION: IDO-high expression by colorectal tumor cells enables certain cancer subsets to initially avoid immune attack and defeat the invasion of T cells via local tryptophan depletion and the production of proapoptotic tryptophan catabolites [13].
• Indoleamine 2,3-dioxygenase (IDO) activity as determined by increases in serum kynurenine was measured in a group of hepatitis C patients treated with consensus interferon (IFN-con1) [14].
• Normal human mammary epithelial cells (HMEC) and MCF-7 breast cancer cells were incubated in serum-free medium supplemented with LA or CLA and cyclooxygenase (indomethacin; INDO) or lipoxygenase (nordihydroguaiaretic acid; NDGA) inhibitors [15].
• The interferon (IFN)-gamma-mediated induction of indoleamine 2,3-dioxygenase (IDO) enzyme, which converts tryptophan into N-formylkynurenine, has been implicated in the inhibition of intracellular pathogens, e.g. Toxoplasma gondii and Chlamydia psittaci, and in the antiproliferative effect of IFN-gamma on tumor cells [16].

Biological context of INDO

• Interferon (IFN)-gamma induces the expression of the indoleamine 2, 3-dioxygenase (INDO) gene in human cells, which plays a role in the inhibitory effect of IFN-gamma on intracellular pathogens and on cell proliferation [17].
• We hypothesized that apoptosis results from L-tryptophan starvation following INDO induction [18].
• Localization of indoleamine 2,3-dioxygenase gene (INDO) to chromosome 8p12-->p11 by fluorescent in situ hybridization [19].
• TNF-alpha and INDO co-treatment was associated with accumulation of cells in G0/G1 cell cycle phase, increased reactive oxygen species production, and elevated caspase-3 activity [3].
• Indoleamine 2,3-dioxygenase (IDO) catalyzes the initial, rate-limiting step of tryptophan (Trp) catabolism along the kynurenine (KYN) pathway, and its induction in cells of the immune system in response to cytokines has been implicated in the regulation of antigen presentation and responses to cell-mediated immune attack [20].

Anatomical context of INDO

• Activation of fibroblasts with rIFN-gamma, rIFN-beta and rTNF-alpha resulted in augmentation of INDO expression and activity leading to 40.0, 25.0 and 27.0 % inhibition of tachyzoite growth, respectively [21].
• In contrast to the parental cell line (2C4), rIFN-gamma was not able to induce the expression of INDO mRNA or microbiostatic activity in any of the mutant cell lines [2].
• Cutting edge: human eosinophils regulate T cell subset selection through indoleamine 2,3-dioxygenase [22].
• We show that human eosinophils constitutively express IDO [22].
• Eosinophils infiltrating asthmatic lung and associated lymphoid tissue exhibited intracellular IDO immunoreactivity [22].

Associations of INDO with chemical compounds

• The inhibition correlated with the level of INDO activity induced and could be reversed by the addition of excess tryptophan to the medium [1].
• Expression of Cd(2+)-induced INDO activity also inhibited thymidine incorporation and led to cytotoxicity in INDO +ve cells but not in INDO -ve cells [1].
• We now report localization of INDO (the gene encoding indolamine 2,3-dioxygenase) by fluorescent in situ hybridization to 8p12-->p11 [19].
• Interferon-gamma (IFN-gamma)-induced indoleamine 2,3-dioxygenase (IDO) activity inhibits the growth of susceptible intracellular pathogens by catalyzing the oxidative cleavage of the indole ring of L-tryptophan and depleting pools of the essential amino acid [23].
• Furthermore, addition of IDO-inhibitor (1-methyl-d-tryptophan) reversed the suppressive effects of IDO on PBMC proliferation in a dose-dependant fashion [24].

Physical interactions of INDO

• This inhibition of IDO was coupled in glioblastoma cells by a complete abrogation of the IFN-gamma-induced toxoplasmastasis in these cells [25].

Regulatory relationships of INDO

• IDO protein expression was upregulated in IFN-gamma-treated islets and accompanied by increased intracellular IDO enzyme activity and the release of KYN into the media [20].
• Thus, CMV infection blocks the inducible nitric oxide synthase pathway activated by IFN-gamma and IL-1beta, but cannot counteract the IFN-induced IDO pathway, which ultimately controls its replication in primary human RPE cells [26].
• These data suggest that CTLA-4 on Treg cells up-regulates IDO expression on decidual and peripheral blood DC and monocytes by the induction of IFN-gamma production [27].
• Interleukin-4 inhibits indoleamine 2,3-dioxygenase expression in human monocytes [28].
• Neither OKT3-stimulated T cells of healthy donors nor myelin basic protein (MBP)-specific T cells of patients with multiple sclerosis (MS) were suppressed by autologous IDO DCs [29].

Other interactions of INDO

• We found that rTNF-alpha was able to induce low levels expression of INDO mRNA in the parental cell line, as well as the cell line lacking functional JAK2 [2].
• Related to this, the NOS inhibitors L-NMMA and aminoguanidine, and the calmodulin antagonist W7 also decreased IDO activity [30].
• Treatment with IL-3, IL-5, GM-CSF, or IFN-gamma alone expressed IDO enzymatic activity (the presence of KYN in supernatants 48 h postculture) [22].
• Immunohistochemical localization showed IDO to be induced in cells of both endocrine, including pancreatic duodenal homeobox 1-positive beta-cells, and nonendocrine origin [20].
• Polyadenylated IDO mRNA accumulation was detected as early as 2 h after IFN stimulation [26].

Analytical, diagnostic and therapeutic context of INDO

• Human fibroblasts (GM637) stably transfected with the sense construct expressed INDO activity after treatment with CdCl2 or ZnSO4, but cells transfected with the antisense construct did not [1].
• Here, we report the possible use of this enzyme to suppress proliferation of immune cells cocultured with IDO-expressing fibroblasts of an allogenic skin substitute [24].
• The results of Western blot analysis, however, revealed a significantly longer (192 h) lasting effect of IFN-gamma on IDO protein level, relative to that of mRNA expression [24].
• Immunoprecipitation analysis showed a nitration of the IDO protein in unstimulated and stimulated U-937 and THP-1 cells [30].
• Strategies to inhibit the IDO pathway may thus assist in breaking tolerance to tumors, and might enhance the efficacy of other immunotherapy strategies by removing unwanted counter-regulation [31].

References