CpG DNA rescue from anti-IgM-induced WEHI-231 B lymphoma apoptosis via modulation of I kappa B alpha and I kappa B beta and sustained activation of nuclear factor-kappa B/c-Rel.
Unmethylated CpG dinucleotides in particular base contexts in oligonucleotides (CpG DNA) rescue WEHI-231 cells from anti-IgM-induced cell cycle arrest and apoptosis. Anti-IgM rapidly elevated the levels of NFkappaB p50/c-Rel heterodimers followed by a decline of p50/c-Rel heterodimers by 3 h and a concomitant increase of p50/p50 homodimers. In contrast, CpG DNA induced and maintained the levels of p50/c-Rel heterodimers in the presence or absence of anti-IgM, while control non-CpG DNA failed to induce NFkappaB activation. Anti-IgM induced IkappaB alpha degradation followed by increased IkappaB alpha protein levels. The levels of IkappaB beta were increased after anti-IgM treatment. In contrast, CpG DNA, but not non-CpG DNA, induced sustained IkappaB alpha and IkappaB beta degradation in the presence or absence of anti-IgM. Inhibition of IkappaB degradation blocked CpG DNA-induced NFkappaB activation and expression of c-myc. Prevention of NFkappaB activation by inhibiting IkappaB degradation also suppressed the ability of CpG DNA to rescue WEHI-231 cells from anti-IgM-induced apoptosis. These results indicate that CpG DNA-mediated sustained activation of NFkappaB depends on the degradation of IkappaB alpha and IkappaB beta and is required for the CpG DNA-mediated anti-apoptosis gene expression and the protection against anti-IgM-induced apoptosis of WEHI-231 cells.
Yi
A K
AK
Department of Internal Medicine, University of Iowa College of Medicine, Iowa City 52242, USA.
Krieg
A M
AM
D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000494:pharmacology*; D000941:Antigens / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D018899:CpG Islands / Q000276:immunology*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000276:immunology; D016259:Genes, myc / Q000276:immunology; D020672:I-kappa B Proteins; D007075:Immunoglobulin M / Q000276:immunology; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000276:immunology*; D051379:Mice; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D020569:Proto-Oncogene Proteins c-rel; D013873:Thionucleotides / Q000494:pharmacology*; D051841:Transcription Factor RelB; D014157:Transcription Factors; D014407:Tumor Cells, Cultured
D000888:Antibodies, Anti-Idiotypic; D000941:Antigens; D004268:DNA-Binding Proteins; C083487:I kappa B beta protein; D020672:I-kappa B Proteins; D007075:Immunoglobulin M; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D009838:Oligodeoxyribonucleotides; D011518:Proto-Oncogene Proteins; D020569:Proto-Oncogene Proteins c-rel; C497594:Relb protein, mouse; D013873:Thionucleotides; D014157:Transcription Factors; C044203:anti-IgM; D000072000:NF-KappaB Inhibitor alpha; D051841:Transcription Factor RelB