title: 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)-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.
authors.affiliation: Department of Bioscience and Biotechnology, Sejong University, Seoul 05006, Korea.
authors.forename: Jae-Wook
authors.initials: JW
authors.lastname: Lee
authors.affiliation: Department of Bioscience and Biotechnology, Sejong University, Seoul 05006, Korea.
authors.forename: Jiyoung
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Kyunggi-do 16419, Korea.
authors.forename: Sung Hee
authors.initials: SH
authors.lastname: Um
authors.affiliation: Department of Bioscience and Biotechnology, Sejong University, Seoul 05006, Korea.
authors.forename: Eun-Yi
authors.initials: EY
authors.lastname: Moon
mesh_terms: D053264:B-Cell Activating Factor / Q000096:biosynthesis* / Q000235:genetics; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D002461:Cell Line, Transformed; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005419:Flavonoids / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000235:genetics; D009842:Oligopeptides / Q000494:pharmacology; D013583:Synovial Membrane / Q000166:cytology / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D053264:B-Cell Activating Factor; D005419:Flavonoids; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009842:Oligopeptides; C505719:TNFSF13B protein, human; D014409:Tumor Necrosis Factor-alpha; C517629:benzyloxycarbonyl-valyl-alanyl-aspartic acid; D048049:Extracellular Signal-Regulated MAP Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one