title: Contact-dependent depletion of hydrogen peroxide by catalase is a novel mechanism of myeloid-derived suppressor cell induction operating in human hepatic stellate cells.
abstract: Myeloid-derived suppressor cells (MDSC) represent a unique cell population with distinct immunosuppressive properties that have been demonstrated to shape the outcome of malignant diseases. Recently, human hepatic stellate cells (HSC) have been reported to induce monocytic-MDSC from mature CD14(+) monocytes in a contact-dependent manner. We now report a novel and unexpected mechanism by which CD14(+)HLADR(low/-) suppressive cells are induced by catalase-mediated depletion of hydrogen peroxide (H2O2). Incubation of CD14(+) monocytes with catalase led to a significant induction of functional MDSC compared with media alone, and H2O2 levels inversely correlated with MDSC frequency (r = -0.6555, p < 0.05). Catalase was detected in primary HSC and a stromal cell line, and addition of the competitive catalase inhibitor hydroxylamine resulted in a dose-dependent impairment of MDSC induction and concomitant increase of H2O2 levels. The NADPH-oxidase subunit gp91 was significantly increased in catalase-induced MDSC as determined by quantitative PCR outlining the importance of oxidative burst for the induction of MDSC. These findings represent a so far unrecognized link between immunosuppression by MDSC and metabolism. Moreover, this mechanism potentially explains how stromal cells can induce a favorable immunological microenvironment in the context of tissue oxidative stress such as occurs during cancer therapy.
authors: Division of Immunity and Infection, Centre for Liver Research and Biomedical Research Unit, National Institute for Health Research, College of Medicine and Dentistry, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom; Department of Internal Medicine 5, Hematology and Oncology, University of Erlangen-Nuremberg, 91054 Erlangen, Germany; and yazid.resheq@uk-erlangen.de.
authors: Yazid J
authors: YJ
authors: Resheq
authors: Division of Immunity and Infection, Centre for Liver Research and Biomedical Research Unit, National Institute for Health Research, College of Medicine and Dentistry, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom;
authors: Ka-Kit
authors: KK
authors: Li
authors: Division of Immunity and Infection, Centre for Liver Research and Biomedical Research Unit, National Institute for Health Research, College of Medicine and Dentistry, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom;
authors: Stephen T
authors: ST
authors: Ward
authors: Division of Immunity and Infection, Centre for Liver Research and Biomedical Research Unit, National Institute for Health Research, College of Medicine and Dentistry, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom;
authors: Annika
authors: A
authors: Wilhelm
authors: Division of Immunity and Infection, Centre for Liver Research and Biomedical Research Unit, National Institute for Health Research, College of Medicine and Dentistry, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom;
authors: Abhilok
authors: A
authors: Garg
authors: Division of Immunity and Infection, Centre for Liver Research and Biomedical Research Unit, National Institute for Health Research, College of Medicine and Dentistry, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom;
authors: Stuart M
authors: SM
authors: Curbishley
authors: Division of Immunity and Infection, Centre for Liver Research and Biomedical Research Unit, National Institute for Health Research, College of Medicine and Dentistry, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom;
authors: Miroslava
authors: M
authors: Blahova
authors: Division of Immunity and Infection, Centre for Liver Research and Biomedical Research Unit, National Institute for Health Research, College of Medicine and Dentistry, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom; Department of Medicine III, University Hospital RWTH Aachen, 25074 Aachen, Germany.
authors: Henning W
authors: HW
authors: Zimmermann
authors: Department of Internal Medicine 5, Hematology and Oncology, University of Erlangen-Nuremberg, 91054 Erlangen, Germany; and.
authors: Regina
authors: R
authors: Jitschin
authors: Department of Internal Medicine 5, Hematology and Oncology, University of Erlangen-Nuremberg, 91054 Erlangen, Germany; and.
authors: Dimitrios
authors: D
authors: Mougiakakos
authors: Department of Internal Medicine 5, Hematology and Oncology, University of Erlangen-Nuremberg, 91054 Erlangen, Germany; and.
authors: Andreas
authors: A
authors: Mackensen
authors: Division of Immunity and Infection, Centre for Liver Research and Biomedical Research Unit, National Institute for Health Research, College of Medicine and Dentistry, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom;
authors: Chris J
authors: CJ
authors: Weston
authors: Division of Immunity and Infection, Centre for Liver Research and Biomedical Research Unit, National Institute for Health Research, College of Medicine and Dentistry, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom;
authors: David H
authors: DH
authors: Adams
mesh_terms: D015153:Blotting, Western; D002374:Catalase / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D002450:Cell Communication / Q000276:immunology; D002460:Cell Line; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D018920:Coculture Techniques; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D006684:HLA-DR Antigens / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000276:immunology* / Q000378:metabolism; D019811:Hydroxylamine / Q000494:pharmacology; D018950:Lipopolysaccharide Receptors / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D022423:Myeloid Cells / Q000276:immunology* / Q000378:metabolism; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D006684:HLA-DR Antigens; D018950:Lipopolysaccharide Receptors; D008562:Membrane Glycoproteins; D019811:Hydroxylamine; D006861:Hydrogen Peroxide; D002374:Catalase; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases