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: Eun-Yi Moon, Kyu Yang Yi, Sunkyung Lee
• Journal: International immunopharmacology (Int Immunopharmacol) Vol. 11 Issue 10 Pg. 1523-33 (Oct 2011) ISSN: 1878-1705 [Electronic] Netherlands
• PMID: 21620999 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier B.V. All rights reserved.

Chemical References

• B-Cell Activating Factor
• B-Cell Activation Factor Receptor
• CD8 Antigens
• Guanidines
• KR33426
• Lipopolysaccharides
• Oxazoles
• Recombinant Fusion Proteins
• Tnfrsf13c protein, mouse
• Tnfsf13b protein, mouse

Topics

• Animals
• Apoptosis (drug effects, immunology)
• B-Cell Activating Factor (genetics, immunology, metabolism)
• B-Cell Activation Factor Receptor (immunology, metabolism)
• B-Lymphocytes (drug effects, immunology, metabolism, pathology)
• CD8 Antigens (genetics, metabolism)
• Cell Line
• Cell Separation
• Drug Evaluation, Preclinical (methods)
• Flow Cytometry
• Guanidines (pharmacology, therapeutic use)
• Humans
• Lipopolysaccharides (immunology, metabolism)
• Lupus Erythematosus, Systemic (drug therapy, genetics, immunology)
• Mice
• Oxazoles (pharmacology, therapeutic use)
• Protein Binding (drug effects, immunology)
• Recombinant Fusion Proteins (genetics, metabolism)
• Signal Transduction (drug effects, immunology)