Nfkb1 activation by the E26 transformation-specific transcription factors PU.1 and Spi-B promotes Toll-like receptor-mediated splenic B cell proliferation.
Generation of antibodies against T-independent and T-dependent antigens requires Toll-like receptor (TLR) engagement on B cells for efficient responses. However, the regulation of TLR expression and responses in B cells is not well understood. PU.1 and Spi-B (encoded by Sfpi1 and Spib, respectively) are transcription factors of the E26 transformation-specific (ETS) family and are important for B cell development and function. It was found that B cells from mice knocked out for Spi-B and heterozygous for PU.1 (Sfpi1(+/-) Spib(-/-) [PUB] mice) proliferated poorly in response to TLR ligands compared to wild-type (WT) B cells. The NF-κB family member p50 (encoded by Nfkb1) is required for lipopolysaccharide (LPS) responsiveness in mice. PUB B cells expressed reduced Nfkb1 mRNA transcripts and p50 protein. The Nfkb1 promoter was regulated directly by PU.1 and Spi-B, as shown by reporter assays and chromatin immunoprecipitation analysis. Occupancy of the Nfkb1 promoter by PU.1 was reduced in PUB B cells compared to that in WT B cells. Finally, infection of PUB B cells with a retroviral vector encoding p50 substantially restored proliferation in response to LPS. We conclude that Nfkb1 transcriptional activation by PU.1 and Spi-B promotes TLR-mediated B cell proliferation.
Department of Microbiology and Immunology and the Centre for Human Immunology, Schulich School of Medicine & Dentistry, and the Collaborative Graduate Program in Developmental Biology, Western University, London, Ontario, Canada Division of Genetics and Development, Children's Health Research Institute, Lawson Research Institute, London, Ontario, Canada.
Stephen K H
SK
Li
Department of Microbiology and Immunology and the Centre for Human Immunology, Schulich School of Medicine & Dentistry, and the Collaborative Graduate Program in Developmental Biology, Western University, London, Ontario, Canada.
Ali K
AK
Abbas
Department of Microbiology and Immunology and the Centre for Human Immunology, Schulich School of Medicine & Dentistry, and the Collaborative Graduate Program in Developmental Biology, Western University, London, Ontario, Canada.
Lauren A
LA
Solomon
Department of Microbiology and Immunology and the Centre for Human Immunology, Schulich School of Medicine & Dentistry, and the Collaborative Graduate Program in Developmental Biology, Western University, London, Ontario, Canada.
Gaëlle M N
GM
Groux
Department of Microbiology and Immunology and the Centre for Human Immunology, Schulich School of Medicine & Dentistry, and the Collaborative Graduate Program in Developmental Biology, Western University, London, Ontario, Canada Division of Genetics and Development, Children's Health Research Institute, Lawson Research Institute, London, Ontario, Canada rdekoter@uwo.ca.
Rodney P
RP
DeKoter
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology* / Q000276:immunology / Q000821:virology; D049109:Cell Proliferation; D008070:Lipopolysaccharides / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052002:NF-kappa B p50 Subunit / Q000235:genetics / Q000276:immunology*; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000276:immunology*; D050783:Proto-Oncogene Proteins c-ets / Q000235:genetics / Q000276:immunology*; D012333:RNA, Messenger / Q000235:genetics; D013154:Spleen / Q000166:cytology*; D051193:Toll-Like Receptors / Q000276:immunology*; D015534:Trans-Activators / Q000276:immunology*; D015533:Transcriptional Activation; D000099232:Proto-Oncogene Protein Spi-1
D008070:Lipopolysaccharides; D052002:NF-kappa B p50 Subunit; D011518:Proto-Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets; D012333:RNA, Messenger; D051193:Toll-Like Receptors; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1; C514177:Spi-B protein, mouse; C073701:Nfkb1 protein, mouse