title: Maintenance of nuclear factor-kappa B/Rel and c-myc expression during CD40 ligand rescue of WEHI 231 early B cells from receptor-mediated apoptosis through modulation of I kappa B proteins.
abstract: Engagement of surface IgM (sIgM) on WEHI 231 murine B lymphoma cells leads to abortive activation and apoptosis, suggesting that this cell line may represent a model for tolerance. Loss of viability in these cells is preceded by an early increase in c-myc RNA levels followed by a decline below control values, implicating c-myc in the control of apoptosis. Costimulation with CD40 ligand (CD40L) has been shown to rescue WEHI 231 cells from anti-sIgM-induced apoptosis, and therefore, the effects of CD40L on c-myc RNA and protein levels were measured. Treatment of these cells with the combination of CD40L and anti-sIgM led to induction and maintenance of elevated levels of c-myc RNA and protein. Since transcriptional regulation of c-myc is mediated through two nuclear factor-kappa B (NF-kappa B) sites in WEHI 231, the effects of CD40L on DNA binding by this family of transcription factors were evaluated. CD40L induced and sustained the levels of NF-kappa B binding to both of these sites, paralleling the changes in c-myc RNA levels. Elevated levels of NF-kappa B were partially achieved through a sustained decrease in the steady state amount of the NF-kappa B/Rel-specific inhibitory protein, I kappa B alpha, and a transient decrease in I kappa B beta. These data lend support to the hypothesis that anti-sIgM-induced apoptosis is caused by a drop in c-myc expression and that an appropriate second signal, such as that provided by CD40L, is able to rescue these cells by inducing NF-kappa B and thereby maintaining c-myc RNA levels.
authors.affiliation: Department of Microbiology, Boston University Medical School, MA 02118, USA.
authors.forename: S L
authors.initials: SL
authors.lastname: Schauer
authors.forename: Z
authors.initials: Z
authors.lastname: Wang
authors.forename: G E
authors.initials: GE
authors.lastname: Sonenshein
authors.forename: T L
authors.initials: TL
authors.lastname: Rothstein
mesh_terms: D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000494:pharmacology; D017209:Apoptosis / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D001483:Base Sequence; D019013:CD40 Antigens / Q000378:metabolism*; D023201:CD40 Ligand; D002453:Cell Cycle / Q000235:genetics / Q000276:immunology; D004268:DNA-Binding Proteins / Q000187:drug effects; D016259:Genes, myc / Q000276:immunology*; D020672:I-kappa B Proteins; D008024:Ligands; D008562:Membrane Glycoproteins / Q000494:pharmacology*; D051379:Mice; D008969:Molecular Sequence Data; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding / Q000276:immunology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D020569:Proto-Oncogene Proteins c-rel; D012333:RNA, Messenger / Q000096:biosynthesis; D011947:Receptors, Antigen, B-Cell / Q000494:pharmacology
chemical_list: D000888:Antibodies, Anti-Idiotypic; D019013:CD40 Antigens; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D008024:Ligands; D008562:Membrane Glycoproteins; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D011518:Proto-Oncogene Proteins; D016271:Proto-Oncogene Proteins c-myc; D020569:Proto-Oncogene Proteins c-rel; D012333:RNA, Messenger; D011947:Receptors, Antigen, B-Cell; C044203:anti-IgM; D000072000:NF-KappaB Inhibitor alpha; D023201:CD40 Ligand