• Title, Summary, Keyword: indoleamine 2,3-dioxygenase

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Tryptophan Metabolite 3-Hydroxyanthranilic Acid Augments TRAIL-Induced Apoptosis in Activated T Cells (트립토판 대사체 3-hydroxyanthranilic acid의 TRAIL-유도 활성 T 세포 사멸 효과)

  • Seo, Su-Kil
    • Journal of Life Science
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    • v.21 no.2
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    • pp.316-321
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    • 2011
  • Generation of tryptophan-derived metabolites by indoleamine 2,3-dioxygenase (IDO) is a potent immunoregulatory mechanism in T cell responses. However, the mechanism remains unclear. We showed that 3-hydroxyanthranilic acid (3-HAA), the most potent metabolite, selectively induced apoptosis in activated T cells, but not in resting T cells. This was not associated with cell cycle arrest. We found that TRAIL expression was selectively induced in activated T cells by treatment of 3-HAA. Blockade of the TRAIL: DR4/DR5 pathway significantly inhibited 3-HAA-mediated T cell death. Our data suggest that TRAIL-induced apoptosis is involved in the mechanism of 3-HAA-mediated T cell death.

Screening of the Inhibitory Activity of Korea Local Plant Extracts against Indoleamine 2,3-dioxygenase (IDO) (한국 자생식물 추출물의 Indoleamine 2,3-dioxygenase (IDO) 저해활성 검색)

  • Jang, Jun-Pil;Jang, Jae-Hyuk;Bae, Eun-Young;Jeong, Sook-Jung;Kim, Hye-Min;Kim, Mee-Ree;Soung, Nak-Kyun;Kim, Bo-Yeon;Ahn, Jong-Seog
    • Korean Journal of Pharmacognosy
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    • v.42 no.4
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    • pp.379-385
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    • 2011
  • Indoleamine 2,3-dioxygenase (IDO) is predicted to be therapeutic target for treatment of cancer and immune disease. Thus, we examined methanol extracts prepared from 156 Korean local plants for their inhibitory effects on IDO in vitro. Among them sixteen extracts showed more than 50% inhibition of IDO activity at the concentration of 30 ${\mu}g/ml$. Especially, the extracts of Platycarya strobilacea, Quercus acutissima, Acer ginnala and Alnus japonica were most potent because their $IC_{50}$ value were 6.5, 8.1, 3.9 and 4.2 ${\mu}g/ml$, respectively.

Cholera Toxin Disrupts Oral Tolerance via NF-κB-mediated Downregulation of Indoleamine 2,3-dioxygenase Expression

  • Kim, Kyoung-Jin;Im, Suhn-Young
    • Biomedical Science Letters
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    • v.23 no.3
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    • pp.175-184
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    • 2017
  • Cholera toxin (CT) is an ADP-ribosylating bacterial exotoxin that has been used as an adjuvant in animal studies of oral immunization. The mechanisms of mucosal immunogenicity and adjuvanticity of CT remain to be established. In this study, we investigated the role of indoleamine 2,3-dioxygenase (IDO), which participates in the induction of immune tolerance, in CT-mediated breakdown of oral tolerance. When IDO-deficient ($IDO^{-/-}$) mice and their littermates were given oral ovalbumin, significant changes in antibody responses, footpad swelling and $CD4^+$ T cell proliferation were not observed in $IDO^{-/-}$ mice. Feeding of CT decreased IDO expression in mesenteric lymph nodes (MLN) and Peyer's patch (PP). CT-induced downregulation of IDO expression was reversed by inhibitors of nuclear factor-kappa B (NF-${\kappa}B$), pyrrolidine dithiocarbamate and p50 small interfering RNA. IDO expression was downregulated by the NF-${\kappa}B$ inducers lipopolysaccharide and tumor necrosis factor-${\alpha}$. CT dampened IDO activity and mRNA expression in dendritic cells from MLN and PP. These data indicate that CT disrupts oral tolerance by activating NF-${\kappa}B$, which in turn downregulates IDO expression. This study betters the understanding of the molecular mechanism underlying CT-mediated abrogation of oral tolerance.

Induction of Indoleamine 2,3-dioxygenase (IDO) Enzymatic Activity Contributes to Interferon-Gamma Induced Apoptosis and Death Receptor 5 Expression in Human Non-small Cell Lung Cancer Cells

  • Chung, Ting Wen;Tan, Kok-Tong;Chan, Hong-Lin;Lai, Ming-Derg;Yen, Meng-Chi;Li, Yi-Ron;Lin, Sheng Hao;Lin, Chi-Chen
    • Asian Pacific Journal of Cancer Prevention
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    • v.15 no.18
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    • pp.7995-8001
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    • 2014
  • Interferon-gamma (IFN-${\gamma}$) has been used to treat various malignant tumors. However, the molecular mechanisms underlying the direct anti-proliferative activity of IFN-${\gamma}$ are poorly understood. In the present study, we examined the in vitro antitumor activity of IFN-${\gamma}$ on two human non-small-cell lung carcinoma (NSCLC) cell lines, H322M and H226. Our findings indicated that IFN-${\gamma}$ treatment caused a time-dependent reduction in cell viability and induced apoptosis through a FADD-mediated caspase-8/tBid/mitochondria-dependent pathway in both cell lines. Notably, we also postulated that IFN-${\gamma}$ increased indoleamine 2,3-dioxygenase (IDO) expression and enzymatic activity in H322M and H226 cells. In addition, inhibition of IDO activity by the IDO inhibitor 1-MT or tryptophan significantly reduced IFN-${\gamma}$-induced apoptosis and death receptor 5 (DR5) expression, which suggests that IDO enzymatic activity plays an important role in the anti-NSCLC cancer effect of IFN-${\gamma}$. These results provide new mechanistic insights into interferon-${\gamma}$ antitumor activity and further support IFN-${\gamma}$ as a potential therapeutic adjuvant for the treatment of NCSLC.

Overexpression of indoleamine 2,3-dioxygenase correlates with regulatory T cell phenotype in acute myeloid leukemia patients with normal karyotype

  • Arandi, Nargess;Ramzi, Mani;Safaei, Fatemeh;Monabati, Ahmad
    • BLOOD RESEARCH
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    • v.53 no.4
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    • pp.294-298
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    • 2018
  • Background Production of immunosuppressive enzymes such as indoleamine 2,3-dioxygenase (IDO) is one of the strategies employed by hematologic malignancies, including acute myeloid leukemia (AML), to circumvent immune surveillance. Moreover, IDO has the ability to convert $CD4^+CD25^-$ conventional T cells into regulatory T cells (Tregs). In this study, we evaluated the expression of IDO in cytogenetically normal acute myeloid leukemia (CN-AML) patients and its correlation with the Treg marker, FOXP3, as well as clinical and laboratory parameters. Methods Thirty-seven newly diagnosed CN-AML patients were enrolled in our study along with 22 healthy individuals. The expression of the IDO and FOXP3 genes was analyzed by SYBR Green real-time PCR. Results Both IDO and FOXP3 were highly upregulated in CN-AML patients compared to control groups (P=0.004 and P=0.031, respectively). A positive correlation was observed between IDO and FOXP3 expression among AML patients (r=0.512, P=0.001). Expression of IDO and FOXP3 showed no significant correlation with laboratory parameters such as white blood cell and platelet counts, hemoglobin levels, bone marrow blast percentage, gender, and FLT3 mutation status (P>0.05). Conclusion Higher IDO expression in CN-AML patients may be associated with an increased Treg phenotype which may promote disease progression and lead to poor prognosis of CN-AML patients.

Matrix Metalloproteinase Inhibitors Attenuate Neuroinflammation Following Focal Cerebral Ischemia in Mice

  • Park, Cheol-Hong;Shin, Tae-Kyeong;Lee, Ho-Youn;Kim, So-Jung;Lee, Won-Suk
    • The Korean Journal of Physiology and Pharmacology
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    • v.15 no.2
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    • pp.115-122
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    • 2011
  • The aim of this study was to investigate whether matrix metalloproteinase (MMP) inhibitors attenuate neuroinflammation in an ischemic brain following photothrombotic cortical ischemia in mice. Male C57BL/6 mice were anesthetized, and Rose Bengal was systemically administered. Permanent focal ischemia was induced in the medial frontal and somatosensory cortices by irradiating the skull with cold white light. MMP inhibitors, such as doxycycline, minocycline, and batimastat, significantly reduced the cerebral infarct size, and the expressions of monocyte chemotactic protein-1 (MCP-1), tumor necrosis factor-${\alpha}$ (TNF-${\alpha}$), and indoleamine 2,3-dioxygenase (IDO). However, they had no effect on the expressions of heme oxygenase-1 and neuroglobin in the ischemic cortex. These results suggest that MMP inhibitors attenuate ischemic brain injury by decreasing the expression levels of MCP-1, TNF-${\alpha}$, and IDO, thereby providing a therapeutic benefit against cerebral ischemia.

Immune Regulatory Function of Dendritic Cells Expressing Indoleamine 2,3-Dioxygenase in Orally Tolerance to Type II Collagen-induced Animal Model (제2형 콜라겐 경구관용 유도 동물모델에서 수지상 세포의 Indoleamine 2,3-dioxygenase의 의존성 관절염 항원 특이 T세포 증식반응 제어 연구)

  • Park, Min-Jung;Min, So-Youn;Park, Kyoung-Su;Cho, Mi-La;CHo, Young-Gyu;Min, Jun-Ki;Yoon, Chong-Hyeon;Park, Sung-Hwa;Kim, Ho-Youn
    • IMMUNE NETWORK
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    • v.5 no.4
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    • pp.221-231
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    • 2005
  • Background: Immune regulatory dendritic cells (DCs) play an important role in maintaining self-tolerance. Recent evidences demonstrate that DCs expressing indoleamine 2,3-dioxygenase (IDO), which is involved in tryptophan catabolism, play an important role in immunoregulation and tolerance and induce T cell apoptosis. This study was devised to examine the role of IDO in the oral tolerance induction in collagen-induced arthritis (CIA) mouse model. Methods: Beginning 2 weeks before immunization, CII was fed six times to DBA/1 mice and the effect on arthritis was assessed. In tolerized mice, $CD11c^+$ DCs were isolated and stimulated with CII, IFN-${\gamma}$, and LPS with or without IDO inhibitor, 1-methyl-DL-tryptophan (1-MT) and IDO expression by $CD11c^+$ DCs was analyzed using FACS and RT-PCR. The expression of IDO, MHC II, CD80, and CD86 by $CD11c^+$ DCs were examined using confocal microscopy. Regulatory effect of $CD11c^+$ DCs on Ag-specific T cell proliferative response to CII was examined by mixed lymphocyte reaction (MLR) with or without 1-MT. Results: The proportion of IDO-expressing $CD11c^+$ DCs was slightly higher in tolerized mice than in CIA mice and significantly increased after stimulation with CII, IFN-${\gamma}$, and LPS in an IDO-dependent manner. On confocal microscopic examination, the expression of IDO was higher and those of MHC II and CD86 were lower in CD11c + DCs from tolerized mice compared to those from CIA mice. On MLR, $CD11c^+$ DCs from tolerized mice inhibited T cell proliferative response to CII in an IDO-dependent manner. Conclusion: Enhanced IDO expression by $CD11c^+$ DCs from tolerized mice may contribute to the regulation of proliferative response of CII-reactive T cells and could be involved in the induction of oral tolerance to CII.

Expression of COX-2 and IDO by Uteroglobin Transduction in NSCLC Cell Lines (비소세포폐암 세포주에서 Uteroglobin Transduction이 COX-2 및 IDO의 발현에 미치는 영향)

  • Park, Gun Min;Lee, Sang-Min;Yim, Jae-Joon;Yang, Seok-Chul;Yoo, Chul Gyu;Lee, Choon-Taek;Han, Sung Koo;Sim, Young-Soo;Kim, Young Whan
    • Tuberculosis and Respiratory Diseases
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    • v.66 no.4
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    • pp.274-279
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    • 2009
  • Background: Uteroglobin (UG) is a secretary protein that has strong immunomodulatory properties, and which is synthesized in most epithelia including lung tissue. Overexpression of UG is associated with decreased expression of cyclooxygenase (COX)-2 and suppression of cancer cell growth. Indoleamine 2,3-dioxygenase (IDO) catalyzes tryptophan along the kynurenine pathway, and both the reduction in local tryptophan and the production of tryptophan metabolites contribute to the immunosuppressive effects of IDO. Methods: In this study, we investigated the pattern of expression of COX-2 and IDO, and the effect of UG transduction in the expression of COX-2 and IDO in several non-small cell lung cancer cell lines, especially A549. Results: Both COX-2 and IDO were constitutionally expressed in A549 and H460 cells, and was reduced by UG transduction. In A549 cells, the slightly increased expression of COX-2 and IDO with the instillation of interferon-gamma (IFN-$\gamma$) was reduced by UG transduction. However, the reduced expression of COX-2 and IDO by UG transduction was not increased with IFN-$\gamma$ instillation in A549 cells. In both the A549 COX-2 sense and the A549 COX-2 anti-sense small interfering RNA (siRNA)-transfected cells, IDO was expressed; expression was reduced by UG transduction, irrespective of the expression of COX-2. Conclusion: The results suggest that the anti-proliferative function of UG may be associated with the immune tolerance pathway of IDO, which is independent of the COX-2 pathway.

Cytokines and Depression (사이토카인과 우울증)

  • Kim, Yong-Ku
    • Korean Journal of Biological Psychiatry
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    • v.15 no.3
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    • pp.175-185
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    • 2008
  • Accumulating evidence has suggested the existence of reciprocal communication between immune, endocrine, and neurotransmitter system. Cytokine hypothesis of depression implies that increased pro-inflammatory cytokine such as -1, IL-6, IL-12, TNF-${\alpha}$, and IFN-${\gamma}$ in major depression, acting neuromodulators, play a key role in the mediation of behavioral, neuroendocrine, and neurochemical disturbances in depression. Concerning the relation between cytokines and serotonin metabolism, pro-inflammatory cytokines have profound effects on the metabolism of brain serotonin through the enzyme indoleamine-2,3-dioxygenase(IDO) that metabolizes tryptophan, the precursor of 5-HT to neurodegenerative quinolinate and neuroprotective kynurenate. The neurodegeneration process is reinforced by the neurotoxic effect of the hypercortisolemia during depression. From this perspective, it is possible that efficacy of antidepressants in the treatment of depression may, at least in part, rely on downregulation of pro-inflammatory cytokine synthesis. So, the use of cytokine synthesis inhibitors or cytokine antagonists may be a new treatment approach in depression. However, at present the question whether cytokines play a causal role in the onset of depression or are mere epiphenomena sustaining depressive symptoms remains to be elucidated. Nevertheless, cytokine hypothesis has created new perspectives in the study of psychological and pathophysiological mechanism that are associated with major depression, as well as the prospect for developing a new generation antidepressants.

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Analysis of Indoleamine 2-3 Dioxygenase (IDO) and EGFR Co-expression in Breast Cancer Tissue by Immunohistochemistry

  • Bi, Wei-Wei;Zhang, Wei-Hua;Yin, Gui-Hua;Luo, Hong;Wang, Shou-Qin;Wang, Hongran;Li, Chao;Yan, Wei-Qun;Nie, De-Zhi
    • Asian Pacific Journal of Cancer Prevention
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    • v.15 no.14
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    • pp.5535-5538
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    • 2014
  • Background: To determine the amount of co-expression of IDO and EGFR in breast cancer patients. Materials and Methods:In order to obtain the distribution of co-expression of IDO and EGFR in breast cancer, we tested 110 breast cancer paraffin tissue blocks with immunohistochemical methods. Then we investigated the relationship between the diagnostic and pathologic characteristics (tumor size, lymph node status, histologic grade, the gene expression of ER, PR, HER2, p53, Ki67 and PCNA) with the situation of co-expression of IDO and EGFR by reviewing the medical records of 32 breast cancer patients. Results: Among 110 breast cancers, 32 cases demonstrated IDO and EGFR co-expression (29.1%), IDO and EGFR synchronous co-expression being found in 19.1% and asynchronous in 10.0%. Conclusions: IDO and EGFR were co-expressed in breast cancer, including synchronous and asynchronous co-expression. The results suggest that considering IDO and EGFR as two indicators for breast cancer treatment or prognosis analysis provides a potential option of individual treatment for the portion of breast cancer patients with co-expression of IDO and EGFR.