title: Induced B7-H1 expression on human renal tubular epithelial cells by the sublytic terminal complement complex C5b-9.
abstract: The co-inhibitory molecule B7-H1 has been broadly detectable on human inflammatory renal tubular epithelial cells (TECs) and is proposed to limit tubular damage through down-regulation of tubulointerstitial infiltration T cell activation. Nevertheless, factors that initiate B7-H1 expression on TECs remain unclarified. The terminal complement complex C5b-9, which deposits diffusely on tubules and glomerules of diseased kidneys, is now recognized as a mediator that triggers cellular activation rather than inducing cell death. Whether the up-regulation of B7-H1 on tubules is also induced by C5b-9 is uncertain. Here, after assembling functional sublytic C5b-9 on the membranes of TECs based on purified complement components, we found that B7-H1 gene transcription and protein synthesis was enhanced by C5b-9. Promoter constructs in a luciferase assay, site-directed mutagenesis and laser scanning confocal microscopy assay (LSCM) revealed that the transcription factor NF-kappaB is primarily responsible for C5b-9-mediated B7-H1 expression. To further detect the physiologic function of B7-H1, triggering B7-H1 with its agonist mAb (clone 5H1) profoundly enhanced Fas expression on C5b-9-treated TECs and thus induced TEC apoptosis. Interestingly, pretreatment of TECs with Fas blocking antibodies prevented this effect. Our results propose that C5b-9 regulates tubular pathogenesis in glomerulonephritis or other renal autoimmune diseases, possibly through enhances cell apoptosis mediated by B7-H1 signals, in addition to it directly promotes tubular damage.
authors.affiliation: Institute of Immunology, PLA, The Third Military Medical University, 400038 Chongqing, PR China.
authors.forename: Yongwen
authors.initials: Y
authors.lastname: Chen
authors.forename: Jingbo
authors.initials: J
authors.lastname: Zhang
authors.forename: Guoning
authors.initials: G
authors.lastname: Guo
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Ruan
authors.forename: Man
authors.initials: M
authors.lastname: Jiang
authors.forename: Shengxi
authors.initials: S
authors.lastname: Wu
authors.forename: Sheng
authors.initials: S
authors.lastname: Guo
authors.forename: Lei
authors.initials: L
authors.lastname: Fei
authors.forename: Yuyu
authors.initials: Y
authors.lastname: Tang
authors.forename: Chengying
authors.initials: C
authors.lastname: Yang
authors.forename: Zhengcai
authors.initials: Z
authors.lastname: Jia
authors.forename: Yuzhang
authors.initials: Y
authors.lastname: Wu
mesh_terms: D015703:Antigens, CD / Q000235:genetics* / Q000378:metabolism; D017209:Apoptosis; D060890:B7-H1 Antigen; D001483:Base Sequence; D015153:Blotting, Western; D002460:Cell Line; D015938:Complement Membrane Attack Complex / Q000378:metabolism*; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism*; D053222:Fas Ligand Protein / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D007684:Kidney Tubules / Q000166:cytology* / Q000378:metabolism; D018613:Microscopy, Confocal; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014158:Transcription, Genetic; D019014:fas Receptor / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D060890:B7-H1 Antigen; C423236:CD274 protein, human; D015938:Complement Membrane Attack Complex; C491901:FAS protein, human; D053222:Fas Ligand Protein; D016328:NF-kappa B; D012333:RNA, Messenger; D019014:fas Receptor