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      Antimalarial drug chloroquine counteracts activation of indoleamine (2,3)-dioxygenase activity in human PBMC

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          Abstract

          Antimalarial chloroquine is also used for the treatment of immune-mediated diseases. The interference of chloroquine with interferon-γ-induced tryptophan breakdown and neopterin production has been investigated in human peripheral blood mononuclear cells (PBMC) in vitro. Micromolar concentrations (2–50 μM) of chloroquine dose-dependently suppressed mitogen-induced tryptophan breakdown in PBMC but not in the myelomonocytic THP-1-Blue cell line, after 48 h of treatment. In stimulated PBMC, neopterin production was super-induced by 10 μM chloroquine, while it was significantly suppressed at a concentration of 50 μM. These anti-inflammatory effects may relate to the therapeutic benefit of chloroquine in inflammatory conditions and may widen the spectrum of its clinical applications.

          Highlights

          ▸ 2–50 μM chloroquine suppresses mitogen-induced tryptophan breakdown in human PBMCs. ▸ The same effect was not seen in the myelomonocytic THP-1-Blue cell line. ▸ The anti-inflammatory property of chloroquine targets T cells more than monocytes. ▸ This anti-inflammatory effect may explain the drug's therapeutic benefit for malaria. ▸ Chloroquine treatment could be of benefit for other chronic inflammatory conditions.

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          Most cited references 34

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          Gene modulation and immunoregulatory roles of interferon gamma.

          Interferon-gamma (IFNgamma) is a central regulator of the immune response and signals via the Janus Activated Kinase (JAK)-Signal Transducer and Activator of Transcription (STAT) pathway. Phosphorylated STAT1 homodimers translocate to the nucleus, bind to Gamma Activating Sequence (GAS) and recruit additional factors to modulate gene expression. A bioinformatics analysis revealed that greater number of putative promoters of immune related genes and also those not directly involved in immunity contain GAS compared to response elements (RE) for Interferon Regulatory Factor (IRF)1, Nuclear factor kappa B (NFkappaB) and Activator Protein (AP)1. GAS is present in putative promoters of well known IFNgamma-induced genes, IRF1, GBP1, CXCL10, and other genes identified were TLR3, VCAM1, CASP4, etc. Analysis of three microarray studies revealed that the expression of a subset of only GAS containing immune genes were modulated by IFNgamma. As a significant correlation exists between GAS containing immune genes and IFNgamma-regulated gene expression, this strategy may identify novel IFNgamma-responsive immune genes. This analysis is integrated with the literature on the roles of IFNgamma in mediating a plethora of functions: anti-microbial responses, antigen processing, inflammation, growth suppression, cell death, tumor immunity and autoimmunity. Overall, this review summarizes our present knowledge on IFNgamma mediated signaling and functions. 2009 Elsevier Ltd. All rights reserved.
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            Hierarchies of NF-κB target-gene regulation.

            Members of the NF-κB family of transcription factors function as dominant regulators of inducible gene expression in almost all cell types in response to a broad range of stimuli, with particularly important roles in coordinating both innate and adaptive immunity. This review summarizes the present knowledge and recent progress toward elucidating the numerous regulatory layers that confer target-gene selectivity in response to an NF-κB-inducing stimulus.
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              Pharmacokinetics of quinine, chloroquine and amodiaquine. Clinical implications.

              Malaria is associated with a reduction in the systemic clearance and apparent volume of distribution of the cinchona alkaloids; this reduction is proportional to the disease severity. There is increased plasma protein binding, predominantly to alpha 1-acid glycoprotein, and elimination half-lives (in healthy adults quinine t1/2z = 11 hours, quinidine t1/2z = 8 hours) are prolonged by 50%. Systemic clearance is predominantly by hepatic biotransformation to more polar metabolites (quinine 80%, quinidine 65%) and the remaining drug is eliminated unchanged by the kidney. Quinine is well absorbed by mouth or following intramuscular injection even in severe cases of malaria (estimated bioavailability more than 85%). Quinine and chloroquine may cause potentially lethal hypotension if given by intravenous injection. Chloroquine is extensively distributed with an enormous total apparent volume of distribution (Vd) more than 100 L/kg, and a terminal elimination half-life of 1 to 2 months. As a consequence, distribution rather than elimination processes determine the blood concentration profile of chloroquine in patients with acute malaria. Parenteral chloroquine should be given either by continuous intravenous infusion, or by frequent intramuscular or subcutaneous injections of relatively small doses. Oral bioavailability exceeds 75%. Amodiaquine is a pro-drug for the active antimalarial metabolite desethylamodiaquine. Its pharmacokinetic properties are similar to these of chloroquine although the Vd is smaller (17 to 34 L/kg) and the terminal elimination half-life is 1 to 3 weeks.
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                Author and article information

                Contributors
                Journal
                FEBS Open Bio
                FEBS Open Bio
                FEBS Open Bio
                Elsevier
                2211-5463
                17 August 2012
                17 August 2012
                2012
                : 2
                : 241-245
                Affiliations
                [a ]Division of Medical Biochemistry, Biocenter, Innsbruck Medical University, 6020 Innsbruck, Austria
                [b ]Division of Biological Chemistry, Biocenter, Innsbruck Medical University, 6020 Innsbruck, Austria
                [c ]Central Institute of Blood Transfusion and Immunology, University Hospital Innsbruck, 6020 Innsbruck, Austria
                Author notes
                [* ]Corresponding author at: Division of Biological Chemistry, Biocenter, Innsbruck Medical University, Rm 4-313, Innrain 80, 6020 Innsbruck, Austria. Tel.: +43 512 9003 70350; fax: +43 512 9003 73330. dietmar.fuchs@ 123456i-med.ac.at
                Article
                FOB43
                10.1016/j.fob.2012.08.004
                3642164
                23650606
                © 2012 Published by Elsevier B.V. on behalf of Federation of European Biochemical Societies.

                This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-No Derivative Works License, which permits non- commercial use, distribution, and reproduction in any medium, provided the original author and source are credited.

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