The rheumatoid arthritis shared epitope increases cellular susceptibility to oxidative stress by antagonizing an adenosine-mediated anti-oxidative pathway

• Published in: Arthritis research & therapy Vol. 9; no. 1; p. R5
• Main Authors: Ling, Song, Li, Zhanguo, Borschukova, Olga, Xiao, Liqun, Pumpens, Paul, Holoshitz, Joseph
• Format: Journal Article
• Language: English
• Published: England National Library of Medicine - MEDLINE Abstracts 01.01.2007; BioMed Central Ltd; BioMed Central
• Subjects: Adenosine - pharmacology; Antioxidants - metabolism; Antioxidants - pharmacology; Arthritis, Rheumatoid - immunology; Arthritis, Rheumatoid - metabolism; B-Lymphocytes - immunology; B-Lymphocytes - metabolism; Disease Susceptibility - immunology; Disease Susceptibility - metabolism; Epitopes, B-Lymphocyte - immunology; Epitopes, B-Lymphocyte - metabolism; Humans; Oxidative Stress - drug effects; Oxidative Stress - physiology; Reactive Oxygen Species - immunology; Reactive Oxygen Species - metabolism; Signal Transduction - drug effects; Signal Transduction - physiology
• ISSN: 1478-6354; 1478-6362; 1478-6354
• DOI: 10.1186/ar2111

We have recently demonstrated that the rheumatoid arthritis (RA) shared epitope (SE) acts as a ligand that triggers nitric oxide (NO) signaling in opposite cells. Given the known pro-oxidative effect of NO and the proposed role of oxidative stress in the pathogenesis of RA, this study explores whether SE-triggered signaling can increase cellular oxidative stress. cAMP levels, adenylyl cyclase activity, and protein kinase A activity were measured using commercial kits. Generation of reactive oxygen species (ROS) was quantified using the fluorochrome dichlorofluorescein diacetate. Oxidative DNA damage was quantified using the single-cell electrophoresis technique. Here, we report that cells exposed to cell surface SE-positive HLA-DR (human leukocyte antigen-DR) molecules, to cell-free recombinant proteins genetically engineered to express the SE motif, or to SE-positive synthetic peptide showed diminished cAMP-dependent signaling, increased ROS levels, and higher vulnerability to oxidative DNA damage. Introduction of single amino acid substitutions into SE-positive peptides revealed a consensus five-amino acid sequence motif of Q/R-K/R-X-X-A that is necessary and sufficient for SE-triggered signaling. The pro-oxidative effect of the SE could be reversed by inhibiting NO production. We conclude that the SE acts as a signaling ligand that activates an NO-mediated pro-oxidative pathway. The potential contribution of this signaling aberration to RA pathogenesis is discussed.