title: Mechanistic analysis of the immunomodulatory effects of a catalytic antioxidant on antigen-presenting cells: implication for their use in targeting oxidation-reduction reactions in innate immunity.
abstract: Reactive oxygen species (ROS) have an indispensable role in controlling the growth of pathogens. Recent evidence also suggests that they can function as second messengers and modulators of the immune system. The identification of many redox-sensitive signal transduction pathways that are necessary for initiating the innate proinflammatory immune response suggests that modulation of these oxidation-reduction reactions may provide a means of therapeutic benefit for controlling inflammatory-mediated diseases. In order to test this hypothesis we employed two catalytic antioxidants (AEOL 10113 and 10150) for the determination of the role of oxidation-reduction reactions in innate immune system activation. Catalytic antioxidants prevented the initiation of the innate immune response in LPS-stimulated macrophages as evidenced by the suppression of proinflammatory cytokines (TNF-alpha, IL-1beta) and ROS (NO2- and O2-). The suppression of proinflammatory cytokine and ROS production correlated with the inhibition of NF-kappaB DNA binding, without any effects on the mitogen-activated protein kinase signaling pathway. Catalytic antioxidants prevented NF-kappaB from binding DNA by an oxidation mechanism that was reversible with the addition of DTT. Although the primary use of these agents was to reduce and scavenge ROS, surprisingly, we also observed the ability of these compounds to exhibit oxidoreductase activity and oxidize redox-sensitive transcription factors such as NF-kappaB. Catalytic antioxidants exhibit antioxidant and pro-oxidant activities and our data further demonstrate the importance of redox balance for the initiation of proinflammation. The coupling of the innate with the adaptive immune response is dependent on TNF-alpha, IL-1beta, NO2-, and O2- generation; therefore, agents like catalytic antioxidants that decrease proinflammatory cytokines and ROS may provide protective effects in diseases in which chronic inflammation plays a pathogenic role.
authors.affiliation: Diabetes Institute, Division of Immunogenetics, Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA 15213-3205, USA.
authors.forename: Hubert M
authors.initials: HM
authors.lastname: Tse
authors.forename: Martha J
authors.initials: MJ
authors.lastname: Milton
authors.forename: Jon D
authors.initials: JD
authors.lastname: Piganelli
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D000938:Antigen-Presenting Cells / Q000187:drug effects* / Q000276:immunology*; D000975:Antioxidants / Q000378:metabolism / Q000494:pharmacology*; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D002384:Catalysis; D002467:Cell Nucleus / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D020672:I-kappa B Proteins / Q000378:metabolism; D007113:Immunity, Innate / Q000187:drug effects* / Q000276:immunology; D007249:Inflammation / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016328:NF-kappa B / Q000378:metabolism; D052002:NF-kappa B p50 Subunit; D010084:Oxidation-Reduction / Q000187:drug effects; D010766:Phosphorylation; D011485:Protein Binding / Q000187:drug effects; D051996:Transcription Factor RelA
chemical_list: D000975:Antioxidants; D022762:CCAAT-Enhancer-Binding Proteins; D016207:Cytokines; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D008070:Lipopolysaccharides; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D051996:Transcription Factor RelA; D004247:DNA