NF-κB-dependent lymphocyte hyperadhesiveness to synovial fibroblasts by hypoxia and reoxygenation: Potential role in rheumatoid arthritis

Hypoxia/reoxygenation has been incriminated as a major factor in the pathogenesis of ischemia/reperfusion injury in various ischemic diseases such as rheumatoid arthritis (RA). In this study, we have investigated the effect of hypoxia/ reoxygenation on the expression of intercellular adhesion molecule-1 (ICAM-1) in synovial fibroblasts and adherence of lymphocytes to synovial fibroblasts. Hypoxia/reoxygenation strongly activated nuclear factor-κB (NF-κB) in synovial fibroblasts to the levels produced by phorbol 12-myristate 13-acetate and caused lymphocyte hyperadhesiveness to synovial fibroblasts as well as up-regulation of ICAM-1, both of which were completely blocked by a NF-κB antagonist (pyrrolidine dithiocarbamate). These results indicate that hypoxia/reoxygenation has a major role in sequestration of inflammatory cells to synovium mediated by the activation of NF-κB. Our data suggest that hypoxia/ reoxygenation could be an important target for the development of new, therapeutic strategies in RA.