B Cell Adhesion to Fibroblast-Like Synoviocytes Is Up-Regulated by Tumor Necrosis Factor-Alpha via Expression of Human Vascular Cell Adhesion Molecule-1 Mediated by B Cell-Activating Factor

Fibroblast-like synoviocytes (FLSs) play a key role in the pathogenesis of rheumatoid arthritis (RA) by producing inflammatory cytokines and interacting with various immune cells, which contribute to cartilage destruction. RA-FLSs activated by tumor necrosis factor alpha (TNF-alpha), exacerbate joint damage by triggering the expression of various inflammatory molecules, including human vascular cell adhesion molecule-1 (hVCAM1) and B cell-activating factor (hBAFF), with a role in maturation and maintenance of B cells. Here, we investigated whether B cell interaction with FLSs could be associated with hVCAM1 expression by TNF-alpha through hBAFF, using WiL2-NS B cells and MH7A synovial cells. TNF-alpha enhanced the expression of hVCAM1 and hBAFF. B cell adhesion to FLSs was increased by treatment with TNF-alpha or hBAFF protein. hVCAM expression was up-regulated by transcriptional activation of the hVCAM1 promoter(-1549 to -54) in MH7A cells treated with hBAFF protein or overexpressed with hBAFF gene. In contrast, hVCAM1 expression was down-regulated by treatment with hBAFF-siRNA. JNK was activated by TNF-alpha treatment. Then, hVCAM1 expression and B cell adhesion to FLSs were reduced by the treatment with JNK inhibitor SP600125. Transcriptional activity of hVCAM1 by the stimulation with TNF-alpha was inhibited by the deletion of -1549 to -229 from the hVCAM1 promoter. hVCAM1 expression and B cell adhesion to FLSs were reduced by treatment with hVCAM1-siRNA. Taken together, these results suggest that B cell adhesion to FLSs is associated with TNF-alpha-induced up-regulation of hVCAM1 expression via hBAFF expression. Thus, the pathological progression of RA may be associated with hVCAM1-mediated interaction of synovial cells with B lymphocytes.