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

Abstract 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)- α -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)-1 α 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-1 α expression were enhanced when MH7A cells were treated with TNF- α . TNF- α -induced BAFF expression decreased in response to HIF-1 α -siRNA, whereas it increased under hypoxia or by overexpressing HIF-1 α . The HIF-1 α 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-1 α . 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-1 α . Taken together, our results demonstrate that BAFF expression to control synovial cell survival was regulated by HIF-1 α binding to the BAFF promoter, and suggest for the first time that HIF-1 α might be involved in the production of inflammatory cytokines to regulate the physiological function of rheumatic FLS.