NF-kappa B is required for surface Ig-induced Fas resistance in B cells.
The susceptibility of primary murine B cells to Fas-mediated apoptosis is regulated in a receptor-specific fashion. Whereas CD40 engagement produces marked sensitivity to Fas killing, engagement of the B cell Ag receptor blocks Fas signaling for cell death in otherwise Fas-sensitive, CD40-stimulated targets and thus induces Fas resistance. The signaling pathway that leads from B cell Ag receptor to Fas resistance has not been fully characterized, but has been shown to depend on new gene expression. NF-kappa B is activated following B cell Ag receptor engagement and is associated with antiapoptosis; thus, it would seem a likely candidate to mediate transcriptional activation for inducible Fas resistance. Inhibition of B cell Ag receptor signaling for NF-kappa B activation completely blocked induction of Fas resistance by anti-Ig, and this same phenotype was observed both with chemical inhibitors such as lactacystin and pyrrolidinedithiocarbamate as well as with an I kappa B alpha dominant negative TAT fusion protein. Antiapoptotic, NF-kappa B-responsive transcripts include two gene products previously implicated in mediating anti-Ig-induced Fas resistance, Bcl-x(L) and FLIP. B cell Ag receptor-induced up-regulation of both these gene products was blocked by NF-kappa B inhibition, suggesting a mechanism by which the loss of nuclear NF-kappa B alters the sensitivity of B cell Ag receptor-stimulated B cells to Fas-mediated apoptosis. These results indicate that activation of NF-kappa B plays a key role in mediating Fas resistance produced by B cell Ag receptor engagement.
Schram
Brian R
BR
Department of Microbiology, School of Medicine and Immunobiology Unit, Evans Memorial Department of Clinical Research, Medical Center, Boston University, MA 02118, USA.
Rothstein
Thomas L
TL
D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000633:toxicity; D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D016175:B-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology; D002478:Cells, Cultured; D015696:Gene Products, tat / Q000235:genetics; D006678:HIV / Q000235:genetics; D020672:I-kappa B Proteins / Q000235:genetics; D007075:Immunoglobulin M / Q000276:immunology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology; D011759:Pyrrolidines / Q000633:toxicity; D011947:Receptors, Antigen, B-Cell / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D013859:Thiocarbamates / Q000633:toxicity; D051020:bcl-X Protein; D019014:fas Receptor / Q000096:biosynthesis / Q000276:immunology* / Q000378:metabolism*; D054322:tat Gene Products, Human Immunodeficiency Virus
D000888:Antibodies, Anti-Idiotypic; C494812:Bcl2l1 protein, mouse; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002352:Carrier Proteins; C506387:Cflar protein, mouse; D015696:Gene Products, tat; D020672:I-kappa B Proteins; D007075:Immunoglobulin M; D007166:Immunosuppressive Agents; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; D011759:Pyrrolidines; D011947:Receptors, Antigen, B-Cell; D011993:Recombinant Fusion Proteins; D013859:Thiocarbamates; C044203:anti-IgM; D051020:bcl-X Protein; D019014:fas Receptor; D054322:tat Gene Products, Human Immunodeficiency Virus; C067713:lactacystin; D000072000:NF-KappaB Inhibitor alpha; C020972:pyrrolidine dithiocarbamic acid; D000111:Acetylcysteine