Synovial cell death is regulated by TNF-α-induced expression of B-cell activating factor through an ERK-dependent increase in hypoxia-inducible factor-1α

B-cell activating factor (BAFF) has a role in the maturation and maintenance of B cells and is associated with rheumatoid arthritis (RA). Here, we investigated whether tumor necrosis factor (TNF)-a-induced BAFF expression controls the survival of fibroblast-like synoviocytes (FLS) and whether their survival can be regulated by TNF-α-mediated upregulation of hypoxia-inducible factor (HIF)-1α using MH7A synovial cells transfected with the SV40 T antigen. More TNF-α-treated cells died compared with the control. Survival was increased by incubation with Z-VAD but inhibited after transfection with BAFF-siRNA. Both BAFF and HIF-1α expression were enhanced when MH7A cells were treated with TNF-α. TNF-α-induced BAFF expression decreased in response to HIF-1α-siRNA, whereas it increased under hypoxia or by overexpressing HIF-1α. The HIF-1α binding site on the BAFF promoter (-693 to - 688 bp) was confirmed by chromatin immunoprecipitation assay to detect the -750 to -501 bp and - 800 to - 601 bp regions. The BAFF promoter increased in response to TNF-α treatment or overexpression of HIF-1α. However, TNF-α-induced BAFF expression and promoter activity decreased after treatment with the ERK inhibitor PD98059. Cell death was enhanced by PD98059 but was inhibited by overexpression of HIF-1α. Taken together, our results demonstrate that BAFF expression to control synovial cell survival was regulated by HIF-1α binding to the BAFF promoter, and suggest for the first time that HIF-1α might be involved in the production of inflammatory cytokines to regulate the physiological function of rheumatic FLS.