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Open Access Highly Accessed Research article

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

Song Ling1, Zhanguo Li12, Olga Borschukova3, Liqun Xiao1, Paul Pumpens3 and Joseph Holoshitz1*

Author Affiliations

1 Department of Internal Medicine, University of Michigan, 1150 W. Medical Center Dr., 5520 MSRB I, Ann Arbor, MI 48109-0680, USA

2 Department of Rheumatology, Beijing Medical University, Beijing, 11 S. Xizhimen Blvd, Beijing, 100044, The People's Republic of China

3 Biomedical Research and Study Center, University of Latvia, Ratsupites 1, Riga, LV-1067, Latvia

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Arthritis Research & Therapy 2006, 9:R5  doi:10.1186/ar2111

Published: 25 January 2007

Abstract

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.