Clofazimine-mediated regulation of human polymorphonuclear leukocyte migration by pro-oxidative inactivation of both leukoattractants and cellular migratory responsiveness |
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| Authors: | R Anderson P Lukey C Van Rensburg U Dippenaar |
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| Affiliation: | 1. Infection, Immunity and Inflammation Research and Teaching Department, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom;2. Department of Immunology and Gene Therapy, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom;3. KU Leuven - Department of Microbiology, Immunology and Transplantation, Rega Institute, Laboratory of Virology and Chemotherapy, Leuven, Belgium;4. Department of Pharmacy, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom;5. Department of Pediatrics, Division of Allergy and Immunology, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia;6. Department of Paediatric Allergy, Immunology and Infectious Diseases, The Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle, United Kingdom;7. Immunology Department, Royal Free Hospital NHS Foundation Trust, London, United Kingdom;8. Institute of Immunity and Transplantation, University College London, London, UK;9. Department of Cardiothoracic Transplantation, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom;10. Department of Microbiology, Virology and Infection Control, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom;11. Unité des Virus Émergents IRD 190, INSERM 1207, Aix-Marseille Université, Marseille, France;12. APHM, Laboratoire de Pharmacocinétique et Toxicologie, Hôpital La Timone, Marseille, France;13. Division of Infection and Immunity, University College London, London, United Kingdom |
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| Abstract: | The effects of clofazimine (0.15-20 micrograms/ml) on the spontaneous and N-formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP)-stimulated migration, membrane-associated oxidative metabolism, degranulation and production of prostaglandin (PG) E2 by human polymorphonuclear in vitro have been investigated. Clofazimine at concentrations of 0.3 microgram/ml and greater significantly increased both the spontaneous and FMLP-stimulated chemiluminescence (CL), hexose monophosphate shunt (HMS) activity, myeloperoxidase-mediated protein iodination, auto-iodination, degranulation and PGE2 production by PMNL. At the same concentrations clofazimine inhibited both random and leukoattractant-induced migration of PMNL. Inhibition of PMNL migration by clofazimine was due to both a cell-directed auto-oxidative mechanism and by functional inactivation of FMLP. Clofazimine mediated inhibition of PMNL migration was prevented by the anti-oxidants cysteine and dapsone but not by the potent inhibitors of PG synthetase indomethacin and piroxicam. Anti-oxidants also protected FMLP from functional inactivation by clofazimine-exposed PMNL. Clofazimine increased both the spontaneous and FMLP-stimulated production of PGE2 by PMNL from four children with chronic granulomatous disease (CGD). Clofazimine is not an oxidising agent nor did it stimulate membrane-associated oxidative metabolism in CGD or NaF-pulsed normal PMNL. These data show that clofazimine-mediated inhibition of PMNL migration is dependent on intact cellular membrane-associated oxidative metabolism. Clofazimine is therefore a pro-oxidative anti-inflammatory agent. |
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