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Unique CD40-mediated biological program in B cell activation requires both type 1 and type 2 NF-kappa B activation pathways

Zarnegar, Brian and He, Jeannie Q. and Oganesyan, Gagik and Hoffmann, Alexander and Baltimore, David and Cheng, Genhong (2004) Unique CD40-mediated biological program in B cell activation requires both type 1 and type 2 NF-kappa B activation pathways. Proceedings of the National Academy of Sciences of the United States of America, 101 (21). pp. 8108-8113. ISSN 0027-8424.

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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.

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Baltimore, David0000-0001-8723-8190
Additional Information:Copyright © 2004 by the National Academy of Sciences. Contributed by David Baltimore, April 15, 2004. We thank Dr. Rolf-Peter Ryseck (Bristol-Myers Squibb, Princeton) and Amgen (Thousand Oaks, CA) for providing p52 knockout mice and hBAFF. We thank Drs. Hajir Dadgostar (University of California, Los Angeles) and Xiao-Feng Qin (M. D. Anderson Cancer Center, Houston) for helpful discussion. J.Q.H. is supported by National Science Foundation GK12 Mathematics and Science Inquiry in Los Angeles Urban Schools Grant DGE-0231998. G.O. is supported by University of California at Los Angeles Medical Scientist Training Program Training Grant GM08042. G.C. is a Research Scholar supported by the Leukemia and Lymphoma Society of America. Part of this work was supported by National Institutes of Health Grants R01 GM57559 and R01 CA87924.
Issue or Number:21
Record Number:CaltechAUTHORS:ZARpnas04
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:852
Deposited By: Tony Diaz
Deposited On:26 Oct 2005
Last Modified:02 Oct 2019 22:37

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