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PMID: 11830667 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Cooperation of multiple signaling pathways in CD40-regulated gene expression in B lymphocytes.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 99 ·No. 3 ·2002-02-05 ·Pages 1497-502

Dadgostar H, Zarnegar B, Hoffmann A, Qin XF, Truong U, Rao G, Baltimore D, Cheng G

Abstract

CD40/CD40L interaction is essential for multiple biological events in T dependent humoral immune responses, including B cell survival and proliferation, germinal center and memory B cell formation, and antibody isotype switching and affinity maturation. By using high-density microarrays, we examined gene expression in primary mouse B lymphocytes after multiple time points of CD40L stimulation. In addition to genes involved in cell survival and growth, which are also induced by other mitogens such as lipopolysaccharide, CD40L specifically activated genes involved in germinal center formation and T cell costimulatory molecules that facilitate T dependent humoral immunity. Next, by examining the roles of individual CD40-activated signal transduction pathways, we dissected the overall CD40-mediated response into genes independently regulated by the individual pathways or collectively by all pathways. We also found that gene down-regulation is a significant part of the overall response and that the p38 pathway plays an important role in this process, whereas the NF-kappa B pathway is important for the up-regulation of primary response genes. Our finding of overlapping independent control of gene expression modules by different pathways suggests, in principle, that distinct biological behaviors that depend on distinct gene expression subsets can be manipulated by targeting specific signaling pathways.

MeSH Terms
Animals Apoptosis B-Lymphocytes/cytology,drug effects,immunology CD40 Antigens/immunology CD40 Ligand/pharmacology Cell Division Cell Survival Cells, Cultured Flow Cytometry Gene Expression Regulation/immunology Lipopolysaccharides/pharmacology Lymphocyte Activation Mice Mice, Inbred C57BL Mice, Knockout Models, Immunological NF-kappa B/deficiency,genetics,physiology RNA, Messenger/genetics Signal Transduction/immunology Spleen/immunology
Chemicals
CD40 Antigens Lipopolysaccharides NF-kappa B RNA, Messenger CD40 Ligand
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Dadgostar Hajir
Molecular Biology Institute and Medical Scientist Training Program, School of Medicine, University of California, Los Angeles, CA 90095, USA.
Zarnegar Brian
Hoffmann Alexander
Qin Xiao-Feng
Truong Uyen
Rao Govinda
Baltimore David
Cheng Genhong
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.032665099
Published
2002-02-05
Pages
1497-502
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC122219
Subset
IM
Grants
NCI NIH HHS · R01 CA087924 · United States
NIGMS NIH HHS · T32 GM008042 · United States
NCI NIH HHS · CA 87924 · United States
NIGMS NIH HHS · GM 08042 · United States
External Links
PubMed source DOI: 10.1073/pnas.032665099 PMC Full Text View journal details
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