title: An increase in B cell apoptosis by interfering BAFF-BAFF-R interaction with small synthetic molecules.
abstract: B cell-activating factor (BAFF) transmitted signals through binding to specific BAFF receptors (BAFF-R) to regulate B cell survival and development. We used MTT assay to examine the cytotoxicity of chemicals, flow cytometry analysis to measure BAFF-BAFF-R interactions, and western blotting to detect BAFF protein. Here, we established screening method to find specific compounds to interfere with BAFF-BAFF-R interactions in WIL2-NS B lymphoblast cells. According to screening (imidazol-4-ylcarbonyl)guanidine or (oxazol-4-ylcarbonyl)guanidine derivatives, we selected KR32592, KR32673, KR33232, KR33341 and KR33426 as candidates to interfere with BAFF-BAFF-R interaction. No cytotoxicity was detected by KR32592, KR33232, and KR33426 at the concentration of 5 μM, and by KR32673, and KR33341 at the concentration of 0.5 μM. Cell population with BAFF-BAFF-R interactions was reduced by the pre-incubation of chemicals with human BAFF-murine CD8 (BAFF-muCD8). Cell population with BAFF-BAFF-R interactions was also decreased by pre-exposure of WIL2-NS cells to chemicals prior to the incubation with BAFF-muCD8. Chemicals also inhibited LPS-stimulated BAFF production from splenocytes. All these effects of chemicals may contribute to the inhibition of BAFF-mediated anti-apoptosis. These data demonstrate that chemicals interfering with BAFF-BAFF-R interaction may be screened with our experimental condition. It suggests that BAFF-BAFF-R interaction could be a chemical target to develop therapeutics for BAFF-mediated autoimmune diseases.
authors.affiliation: Department of Bioscience and Biotechnology, Sejong University, Seoul 143-747, Republic of Korea. eunyimoon@sejong.ac.kr
authors.forename: Eun-Yi
authors.initials: EY
authors.lastname: Moon
authors.forename: Kyu Yang
authors.initials: KY
authors.lastname: Yi
authors.forename: Sunkyung
authors.initials: S
authors.lastname: Lee
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D053264:B-Cell Activating Factor / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D053265:B-Cell Activation Factor Receptor / Q000276:immunology / Q000378:metabolism; D001402:B-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016827:CD8 Antigens / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002469:Cell Separation; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005434:Flow Cytometry; D006146:Guanidines / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D008070:Lipopolysaccharides / Q000276:immunology / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D051379:Mice; D010080:Oxazoles / Q000494:pharmacology* / Q000627:therapeutic use; D011485:Protein Binding / Q000187:drug effects / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology
chemical_list: D053264:B-Cell Activating Factor; D053265:B-Cell Activation Factor Receptor; D016827:CD8 Antigens; D006146:Guanidines; C569343:KR33426; D008070:Lipopolysaccharides; D010080:Oxazoles; D011993:Recombinant Fusion Proteins; C486662:Tnfrsf13c protein, mouse; C505720:Tnfsf13b protein, mouse