title: Superoxide attenuates macrophage apoptosis by NF-kappa B and AP-1 activation that promotes cyclooxygenase-2 expression.
abstract: Macrophages are a major source of cytokines and proinflammatory radicals such as superoxide. These mediators can be both produced and utilized by macrophages in autocrine-regulatory pathways. Therefore, we studied the potential role of oxygen radical-regulatory mechanisms in reprogramming macrophage apoptosis. Preactivation of RAW 264.7 cells with a nontoxic dose of the redox cycler 2,3-dimethoxy-1,4-naphthoquinone (5 microM) for 15 h attenuated S-nitrosoglutathione (1 mM)-initiated apoptotic cell death and averted accumulation of the tumor suppressor p53, which is indicative for macrophage apoptosis. Preactivation with superoxide promoted cyclooxygenase-2 induction that was NF-kappa B and AP-1 mediated. NF-kappa B activation was confirmed by p50/p65-heterodimer formation, I kappa B-alpha degradation, and stimulation of a NF-kappa B luciferase reporter construct. Furthermore, a NF-kappa B decoy approach abrogated cyclooxygenase-2 (Cox-2) expression as well as inducible protection. The importance of AP-1 for superoxide-mediated Cox-2 expression and cell protection was substantiated by using the extracellular signal-regulated kinase-inhibitor PD98059 and the p38-inhibitor SB203580, which blocked Cox-2 expression. In corroboration, Cox-2 expression was hindered by a dominant-negative c-jun mutant (TAM67). Protection from apoptosis was verified in human macrophages with the notion that superoxide promoted Cox-2 expression, which in turn attenuated nitric oxide-evoked caspase activation. We conclude that the sublethal generation of oxygen radicals reprograms macrophages by NF-kappa B and AP-1 activation. The resulting hyporesponsiveness reveals an attenuated apoptotic program in association with Cox-2 expression.
authors.affiliation: Department of Medicine IV, Experimental Division, Faculty of Medicine, University of Erlangen-Nürnberg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: von Knethen
authors.forename: D
authors.initials: D
authors.lastname: Callsen
authors.forename: B
authors.initials: B
authors.lastname: Brüne
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D002460:Cell Line; D051546:Cyclooxygenase 2; D004305:Dose-Response Relationship, Drug; D007527:Isoenzymes / Q000096:biosynthesis* / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism* / Q000502:physiology; D009285:Naphthoquinones / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis* / Q000378:metabolism; D013481:Superoxides / Q000494:pharmacology*; D018808:Transcription Factor AP-1 / Q000378:metabolism* / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D000276:Adjuvants, Immunologic; D007527:Isoenzymes; D016328:NF-kappa B; D009285:Naphthoquinones; D018808:Transcription Factor AP-1; D016159:Tumor Suppressor Protein p53; D013481:Superoxides; D009569:Nitric Oxide; C063002:2,3-dimethoxy-1,4-naphthoquinone; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases