title: Induction of copper/zinc-superoxide dismutase by CCL5/CCR5 activation causes tumour necrosis factor-alpha and reactive oxygen species production in macrophages.
abstract: Using two-dimensional sodium dodecyl sulphate-polyacrylamide gel electrophoresis, we found that copper/zinc superoxide dismutase (Cu/Zn-SOD, SOD-1) was induced in constructed CCR5 stably transfected HEK 293 cells, but not in mock cells, treated with CCL5. CCL5-induced SOD-1 expression was also confirmed in HEK 293-CCR5 cells and CCR5-positive granulocyte-macrophage colony-stimulating factor-induced human macrophages and murine macrophage RAW264.7 cells. CCL5 and CCR5 interaction induced SOD-1 expression mainly via MEK-ERK activation. In addition, we provided evidence that upregulation of SOD-1 by CCL5/CCR5 activation occurred in parallel with the increased release of tumour necrosis factor-alpha and nitric oxide and production of intracellular reactive oxygen species as well as enhanced nuclear factor-kappaB transcriptional activity in CCR5-positive RAW264.7 cells. Conversely, the MEK1/2 inhibitor PD98059 significantly inhibited SOD-1 expression with the decrease of these biological responses. More importantly, inhibition of SOD-1 activity by disulfiram also strongly inhibited the CCL5-induced biological effects. These data suggest that SOD-1 mediates CCR5 activation by CCL5 and that pharmacological modulation of SOD-1 may be beneficial to CCR5-associated diseases.
authors.affiliation: Department of Biochemical Pharmacy, College of Pharmacy, Second Military Medical University, Shanghai, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Qiu
authors.forename: Li
authors.initials: L
authors.lastname: Ding
authors.forename: Jin
authors.initials: J
authors.lastname: Huang
authors.forename: Dong
authors.initials: D
authors.lastname: Wang
authors.forename: Junping
authors.initials: J
authors.lastname: Zhang
authors.forename: Baoyu
authors.initials: B
authors.lastname: Guo
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D018946:Chemokine CCL5 / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D048728:MAP Kinase Kinase Kinase 1 / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D048730:MAP Kinase Kinase Kinase 2 / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D009569:Nitric Oxide / Q000819:agonists / Q000276:immunology / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000819:agonists / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D019713:Receptors, CCR5 / Q000819:agonists / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000096:biosynthesis*; D000072105:Superoxide Dismutase-1; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000819:agonists / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology; D000077191:Wortmannin; D000097782:NF-kappaB-Inducing Kinase
chemical_list: D000730:Androstadienes; D018946:Chemokine CCL5; D048049:Extracellular Signal-Regulated MAP Kinases; D005419:Flavonoids; D048728:MAP Kinase Kinase Kinase 1; D048730:MAP Kinase Kinase Kinase 2; D009569:Nitric Oxide; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D017382:Reactive Oxygen Species; D019713:Receptors, CCR5; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D014409:Tumor Necrosis Factor-alpha; D000077191:Wortmannin; D000097782:NF-kappaB-Inducing Kinase; C483024:CCL5 protein, human; C000606290:SOD1 protein, human; C000606291:Sod1 protein, mouse; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one