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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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          Gene modulation and immunoregulatory roles of interferon gamma.

          Banishree Saha, S. Jyothi Prasanna, Bhagawat Chandrasekar … (2010)
          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.

            Stephen T. Smale (2011)
            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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              Chloroquine inhibits lysosomal enzyme pinocytosis and enhances lysosomal enzyme secretion by impairing receptor recycling

              JH Grubb, WS Sly, A Lira-Noriega (1980)
              Adsorptive pinocytosis of acid hydrolases by fibroblasts depends on phosphomannosyl recognition markers on the enzymes and high-affinity pinocytosis receptors on the cell surface. In this study, beta- glucuronidase binding to the cell surface of attached fibroblasts was found to be saturable and inhibitable by mannose-6-phosphate (Man-6-P). Dissociation of cell-bound beta-glucuronidase occurred very slowly at neutral pH, but was greatly accelerated by lowering the pH below 6.0, or by exposure to Man-6-P. Comparison of the maximal cell surface binding and the observed rate of enzyme pinocytosis suggests that the pinocytosis receptors are replaced or reused about every 5 min. Enzyme pinocytosis was not affected by inhibition of new protein synthesis for several hours, suggesting a large pool of internal receptors and/or reuse of internalized receptors. Chloroquine treatment of normal human fibroblasts had three effects: (a) greatly enhanced secretion of newly synthesized acid hydrolases bearing the recognition marker for uptake, (b) depletion of enzyme-binding sites from the cell surface, and (c) inhibition of pinocytosis of exogenous enzyme. Only the third effect was seen in I-cell disease fibroblasts, which were also less sensitive than control cells to this effect. These observations are consistent with a model for transport of acid hydrolases that proposes that delivery of newly synthesized acid hydrolases to lysosomes requires the phosphomannosyl recognition marker on the enzymes, and intracellular receptors that segregate receptor-bound enzymes into vesicles for transport to lysosomes. This model explains how chloroquine, which raises intralysosomal pH, can disrupt both the intracellular pathway for newly synthesized acid hydrolases, and the one for uptake of exogenous enzyme by cell surface pinocytosis receptors.
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                Author and article information

                Contributors
                Dietmar Fuchs
                Journal
                Journal ID (nlm-ta): FEBS Open Bio
                Journal ID (iso-abbrev): FEBS Open Bio
                Title: FEBS Open Bio
                Publisher: Elsevier
                ISSN (Electronic): 2211-5463
                Publication date PMC-release: 17 August 2012
                Publication date (Electronic): 17 August 2012
                Publication date Collection: 2012
                Volume: 2
                Pages: 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
                Publisher ID: FOB43
                DOI: 10.1016/j.fob.2012.08.004
                PMC ID: 3642164
                PubMed ID: 23650606
                SO-VID: 5ac72262-11cd-44c1-8093-5d961e19c296
                Copyright © © 2012 Published by Elsevier B.V. on behalf of Federation of European Biochemical Societies.
                License:

                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.

                History
                Date received : 9 July 2012
                Date revision received : 8 August 2012
                Date accepted : 13 August 2012
                Categories
                Subject: Article

                Keywords: chloroquine,indoleamine (2,3)-dioxygenase (ido),tryptophan,neopterin,pbmc
                Data availability:
                Keywords: chloroquine, indoleamine (2,3)-dioxygenase (ido), tryptophan, neopterin, pbmc

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