1. Induced B7-H1 expression on human renal tubular epithelial cells by the sublytic terminal complement complex C5b-9.
- Author
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Chen Y, Zhang J, Guo G, Ruan Z, Jiang M, Wu S, Guo S, Fei L, Tang Y, Yang C, Jia Z, and Wu Y
- Subjects
- Antigens, CD metabolism, Apoptosis, B7-H1 Antigen, Base Sequence, Blotting, Western, Cell Line, Epithelial Cells cytology, Fas Ligand Protein metabolism, Flow Cytometry, Humans, Kidney Tubules metabolism, Microscopy, Confocal, Molecular Sequence Data, NF-kappa B metabolism, Promoter Regions, Genetic genetics, RNA, Messenger genetics, RNA, Messenger metabolism, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, Transcription, Genetic, fas Receptor metabolism, Antigens, CD genetics, Complement Membrane Attack Complex metabolism, Epithelial Cells metabolism, Kidney Tubules cytology
- 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.
- Published
- 2009
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