The rheumatoid arthritis shared epitope increases cellular susceptibility to oxidative stress by antagonizing an adenosine-mediated anti-oxidative pathway
dc.contributor.author | Ling, Song | |
dc.contributor.author | Li, Zhanguo | |
dc.contributor.author | Borschukova, Olga | |
dc.contributor.author | Xiao, Liqun | |
dc.contributor.author | Pumpens, Paul | |
dc.contributor.author | Holoshitz, Joseph | |
dc.date.accessioned | 2015-08-07T17:36:09Z | |
dc.date.available | 2015-08-07T17:36:09Z | |
dc.date.issued | 2007-01-25 | |
dc.identifier.citation | Arthritis Research & Therapy. 2007 Jan 25;9(1):R5 | |
dc.identifier.uri | https://hdl.handle.net/2027.42/112601 | en_US |
dc.description.abstract | 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. | |
dc.title | The rheumatoid arthritis shared epitope increases cellular susceptibility to oxidative stress by antagonizing an adenosine-mediated anti-oxidative pathway | |
dc.type | Article | en_US |
dc.description.bitstreamurl | http://deepblue.lib.umich.edu/bitstream/2027.42/112601/1/13075_2006_Article_1975.pdf | |
dc.identifier.doi | 10.1186/ar2111 | en_US |
dc.language.rfc3066 | en | |
dc.rights.holder | Ling et al. | |
dc.date.updated | 2015-08-07T17:36:10Z | |
dc.owningcollname | Interdisciplinary and Peer-Reviewed |
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