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)-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.
Highlights
Synovial hyperplasia and destruction of cartilage and bone are characteristics of rheumatoid arthritis (RA).[1]
Hypoxia-inducible factor-1α (HIF-1α) and BAFF are highly expressed in the joints of patients with RA, the relationship between these two hBAFF to GAPDH hBAFF to GAPDH
Synovial cells isolated from patients with RA were treated with tumor necrosis factor (TNF)-α for 1, 3, 6, 9, 12 h, and hBAFF expression was highest after the 6 h treatment
Summary
Synovial hyperplasia and destruction of cartilage and bone are characteristics of rheumatoid arthritis (RA).[1]. Hypoxia-inducible factor-1α (HIF-1α), which is a regulator of angiogenesis, tumor growth, and glucose metabolism, is a wellknown transcription factor in cancers.[6,7] HIF-1α has an important role in the pathogenesis of RA.[8] High expression levels of HIF-1α are detected in the intimal synovium of patients with RA and are localized in the nucleus and cytoplasm of synoviocytes.[9] HIF-1α is normally degraded under normoxic conditions by the ubiquitin–proteasome pathway;[10] it accumulates under normoxic conditions in an inflammatory environment.[11] Various immune cells, including macrophages,. T cells, B cells, and plasma cells are recruited to the layer that lines the synovium during the progression of RA.[12] angiogenesis occurs, a malfunctioning vascular system maintains the hypoxic conditions.[13,14] Hypoxia-exposed macrophages produce additional quantities of proinflammatory cytokines, such as tumor necrosis factor (TNF)-α.15. Synovial macrophages and synoviocytes produce abundant pro- and anti-inflammatory cytokines, such as TNF-α, interleukin (IL)-1, IL-6, and transforming growth factor-β.3,16,17 TNF-α regulates other cytokines, destroys joint tissue,[18,19] and stabilizes HIF-1α under normoxic conditions.[20]
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