TGF beta 1 inhibits NF-kappa B/Rel activity inducing apoptosis of B cells: transcriptional activation of I kappa B alpha.
TGF beta 1 treatment of B cell lymphomas decreases c-myc gene expression and induces apoptosis. Since we have demonstrated NF-kappa/Rel factors play a key role in transcriptional control of c-myc, we explored the effects of TGF beta1 on WEHI 231 immature B cells. A reduction in NF-kappa B/Rel activity followed TGF beta 1 treatment. In WEHI 231 and CH33 cells, we observed an increase in I kappa B alpha, a specific NF-kappa B/Rel inhibitor, due to transcriptional induction. Engagement of surface CD40 or ectopic c-Rel led to maintenance of NF-kappa B/Rel and c-Myc expression and protection of WEHI 231 cells from TGF beta 1-mediated apoptosis. Ectopic c-Myc expression overrode apoptosis induced by TGF beta 1. Thus, downmodulation of NF-kappa B/Rel reduces c-Myc expression, which leads to apoptosis in these immature B cell models of clonal deletion. The inhibition of NF-kappa B/Rel activity represents a novel TGF beta signaling mechanism.
Arsura
M
M
Department of Biochemistry, Boston University School of Medicine, Massachusetts 02118, USA.
Wu
M
M
Sonenshein
G E
GE
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001402:B-Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D023201:CD40 Ligand; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D016259:Genes, myc / Q000276:immunology; D008024:Ligands; D008562:Membrane Glycoproteins / Q000494:pharmacology; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics*; D020569:Proto-Oncogene Proteins c-rel; D012333:RNA, Messenger / Q000096:biosynthesis; D051841:Transcription Factor RelB; D014157:Transcription Factors; D014158:Transcription, Genetic / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D008024:Ligands; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; D020569:Proto-Oncogene Proteins c-rel; D012333:RNA, Messenger; C497594:Relb protein, mouse; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D023201:CD40 Ligand; D051841:Transcription Factor RelB