title: Cooperation of multiple signaling pathways in CD40-regulated gene expression in B lymphocytes.
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.
authors.affiliation: Molecular Biology Institute and Medical Scientist Training Program, School of Medicine, University of California, Los Angeles, CA 90095, USA.
authors.forename: Hajir
authors.initials: H
authors.lastname: Dadgostar
authors.forename: Brian
authors.initials: B
authors.lastname: Zarnegar
authors.forename: Alexander
authors.initials: A
authors.lastname: Hoffmann
authors.forename: Xiao-Feng
authors.initials: XF
authors.lastname: Qin
authors.forename: Uyen
authors.initials: U
authors.lastname: Truong
authors.forename: Govinda
authors.initials: G
authors.lastname: Rao
authors.forename: David
authors.initials: D
authors.lastname: Baltimore
authors.forename: Genhong
authors.initials: G
authors.lastname: Cheng
mesh_terms: D000818:Animals; D017209:Apoptosis; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D019013:CD40 Antigens / Q000276:immunology*; D023201:CD40 Ligand / Q000494:pharmacology; D002455:Cell Division; D002470:Cell Survival; D002478:Cells, Cultured; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000276:immunology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018448:Models, Immunological; D016328:NF-kappa B / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics; D015398:Signal Transduction / Q000276:immunology*; D013154:Spleen / Q000276:immunology
chemical_list: D019013:CD40 Antigens; D008070:Lipopolysaccharides; D016328:NF-kappa B; D012333:RNA, Messenger; D023201:CD40 Ligand