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Influence of immunosuppressive agents on tryptophan degradation and neopterin production in human peripheral blood mononuclear cells.
Transpl Immunol. 2011 Sep; 25(2-3):119-23.TI

Abstract

The anti-proliferative and immunomodulatory enzyme indoleamine 2,3-dioxygenase (IDO) degrades the essential amino acid tryptophan via the kynurenine pathway. IDO is stimulated during cellular immune responses preferentially by Th1-type cytokine interferon-γ (IFN-γ). IDO activity is estimated by calculating the kynurenine to tryptophan ratio (Kyn/Trp). In human monocyte-derived macrophages and dendritic cells, GTP-cyclohydrolase I is induced in parallel to IDO and produces neopterin. This study investigated the effects of common immunosuppressants on freshly isolated human peripheral blood mononuclear cells (PBMC) in vitro. PBMC were incubated with compounds for 30 min and then either left unstimulated or stimulated with mitogen phytohaemagglutinin (PHA). Concentrations of tryptophan, kynurenine and neopterin were measured in supernatants after 48 h. Kyn/Trp, neopterin and IFN-γ concentrations were significantly higher in PHA-stimulated vs. unstimulated PBMC. Tacrolimus (FK506), cyclosporine A (CsA), sirolimus and methylprednisolone dose-dependently inhibited tryptophan degradation and neopterin production. FK506, CsA and sirolimus showed significant inhibition at concentrations as low as 0.1 μg/ml, whereas prednisolone and methylprednisolone required higher doses to suppress tryptophan degradation. Mycophenolate-mofetil suppressed neopterin formation more efficiently than Kyn/Trp. All tested drugs also strongly decreased mitogen-induced IFN-γ concentrations. Overall the investigated immunosuppressants are effective to inhibit IDO activity and neopterin production in a similar and dose-dependent manner, however with some differences in IC50s when comparing individual compounds. The corresponding changes of IFN-γ concentrations are in line with its role as a trigger of both biochemical changes.

Authors+Show Affiliations

Division of Biological Chemistry, Biocenter, Innsbruck Medical University, Innsbruck, Austria.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

21742032

Citation

Schroecksnadel, Sebastian, et al. "Influence of Immunosuppressive Agents On Tryptophan Degradation and Neopterin Production in Human Peripheral Blood Mononuclear Cells." Transplant Immunology, vol. 25, no. 2-3, 2011, pp. 119-23.
Schroecksnadel S, Sucher R, Kurz K, et al. Influence of immunosuppressive agents on tryptophan degradation and neopterin production in human peripheral blood mononuclear cells. Transpl Immunol. 2011;25(2-3):119-23.
Schroecksnadel, S., Sucher, R., Kurz, K., Fuchs, D., & Brandacher, G. (2011). Influence of immunosuppressive agents on tryptophan degradation and neopterin production in human peripheral blood mononuclear cells. Transplant Immunology, 25(2-3), 119-23. https://doi.org/10.1016/j.trim.2011.06.005
Schroecksnadel S, et al. Influence of Immunosuppressive Agents On Tryptophan Degradation and Neopterin Production in Human Peripheral Blood Mononuclear Cells. Transpl Immunol. 2011;25(2-3):119-23. PubMed PMID: 21742032.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Influence of immunosuppressive agents on tryptophan degradation and neopterin production in human peripheral blood mononuclear cells. AU - Schroecksnadel,Sebastian, AU - Sucher,Robert, AU - Kurz,Katharina, AU - Fuchs,Dietmar, AU - Brandacher,Gerald, Y1 - 2011/07/01/ PY - 2011/02/18/received PY - 2011/06/16/revised PY - 2011/06/16/accepted PY - 2011/7/12/entrez PY - 2011/7/12/pubmed PY - 2012/2/9/medline SP - 119 EP - 23 JF - Transplant immunology JO - Transpl. Immunol. VL - 25 IS - 2-3 N2 - The anti-proliferative and immunomodulatory enzyme indoleamine 2,3-dioxygenase (IDO) degrades the essential amino acid tryptophan via the kynurenine pathway. IDO is stimulated during cellular immune responses preferentially by Th1-type cytokine interferon-γ (IFN-γ). IDO activity is estimated by calculating the kynurenine to tryptophan ratio (Kyn/Trp). In human monocyte-derived macrophages and dendritic cells, GTP-cyclohydrolase I is induced in parallel to IDO and produces neopterin. This study investigated the effects of common immunosuppressants on freshly isolated human peripheral blood mononuclear cells (PBMC) in vitro. PBMC were incubated with compounds for 30 min and then either left unstimulated or stimulated with mitogen phytohaemagglutinin (PHA). Concentrations of tryptophan, kynurenine and neopterin were measured in supernatants after 48 h. Kyn/Trp, neopterin and IFN-γ concentrations were significantly higher in PHA-stimulated vs. unstimulated PBMC. Tacrolimus (FK506), cyclosporine A (CsA), sirolimus and methylprednisolone dose-dependently inhibited tryptophan degradation and neopterin production. FK506, CsA and sirolimus showed significant inhibition at concentrations as low as 0.1 μg/ml, whereas prednisolone and methylprednisolone required higher doses to suppress tryptophan degradation. Mycophenolate-mofetil suppressed neopterin formation more efficiently than Kyn/Trp. All tested drugs also strongly decreased mitogen-induced IFN-γ concentrations. Overall the investigated immunosuppressants are effective to inhibit IDO activity and neopterin production in a similar and dose-dependent manner, however with some differences in IC50s when comparing individual compounds. The corresponding changes of IFN-γ concentrations are in line with its role as a trigger of both biochemical changes. SN - 1878-5492 UR - https://www.unboundmedicine.com/medline/citation/21742032/Influence_of_immunosuppressive_agents_on_tryptophan_degradation_and_neopterin_production_in_human_peripheral_blood_mononuclear_cells_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0966-3274(11)00065-7 DB - PRIME DP - Unbound Medicine ER -