Unique CD40-mediated biological program in B cell activation requires both type 1 and type 2 NF-kappaB activation pathways.
B lymphocytes can be activated by many different stimuli. However, the mechanisms responsible for the signaling and functional specificities of individual stimuli remain to be elucidated. Here, we have compared the contribution of the type 1 (p50-dependent) and type 2 (p52-dependent) NF-kappaB activation pathways to cell survival, proliferation, homotypic aggregation, and specific gene regulation of murine primary B lymphocytes. Whereas lipopolysaccharide (LPS) and B cell activation factor (BAFF) mainly activate the type 1 or type 2 pathways, respectively, CD40 ligand (CD40L) strongly activates both. Rescue of spontaneous apoptosis is diminished in p52(-/-) B cells after BAFF stimulation and in p50(-/-)c-Rel(-/-) B cells after LPS stimulation. Interestingly, significant CD40-induced B cell survival is still observed even in p50(-/-)c-Rel(-/-)p65(-/+) B cells, which is correlated with the ability of CD40L to up-regulate Bcl-x(L) expression in these cells. CD40L- and LPS-induced B cell proliferation, as well as up-regulation of proliferation-related genes, however, are greatly reduced in c-Rel(-/-) and p50(-/-)c-Rel(-/-) B cells but are normal in p52(-/-) B cells. We have further demonstrated that both c-Rel and p52 are required for CD40-mediated B cell homotypic aggregation, which explains well why neither LPS nor BAFF has this function. Overall, our studies suggest that both type 1 and type 2 NF-kappaB pathways contribute to the gene expression and biological program unique for CD40 in B cell activation.
Zarnegar
Brian
B
Department of Microbiology, Immunology, and Molecular Genetics, Jonsson Comprehensive Cancer Center and Molecular Biology Institute, University of California, Los Angeles, CA 90095, USA.
He
Jeannie Q
JQ
Oganesyan
Gagik
G
Hoffmann
Alexander
A
Baltimore
David
D
Cheng
Genhong
G
D000818:Animals; D053264:B-Cell Activating Factor; D001402:B-Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D019013:CD40 Antigens / Q000378:metabolism*; D023201:CD40 Ligand / Q000378:metabolism; D002449:Cell Aggregation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000187:drug effects; D008070:Lipopolysaccharides / Q000494:pharmacology; D008565:Membrane Proteins / Q000494:pharmacology; D051379:Mice; D016328:NF-kappa B / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D052002:NF-kappa B p50 Subunit; D020569:Proto-Oncogene Proteins c-rel / Q000172:deficiency / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D053264:B-Cell Activating Factor; D019013:CD40 Antigens; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D020569:Proto-Oncogene Proteins c-rel; C505720:Tnfsf13b protein, mouse; D014409:Tumor Necrosis Factor-alpha; D023201:CD40 Ligand