p38 MAPK is required for CD40-induced gene expression and proliferation in B lymphocytes.
We have investigated the activation of the p38 MAPK pathway in response to CD40 engagement in multiple B cell lines and in human tonsillar B cells to define the role of p38 MAPK in proliferation, NF-kappaB activation and gene expression. Cross-linking CD40 rapidly stimulates both p38 MAPK and its downstream effector, MAPKAPK-2. Inhibition of p38 MAPK activity in vivo with the specific cell-permeable inhibitor, SB203580, under conditions that completely prevented MAPKAPK-2 activation, strongly perturbed CD40-induced tonsillar B cell proliferation while potentiating the B cell receptor (BCR)-driven proliferative response. SB203580 also significantly reduced expression of a reporter gene driven by a minimal promoter containing four NF-kappaB elements, indicating a requirement for the p38 MAPK pathway in CD40-induced NF-kappaB activation. However, CD40-mediated NF-kappaB binding was not affected by SB203580, suggesting that NF-kappaB may not be a direct target for the CD40-induced p38 MAPK pathway. In addition, SB203580 selectively reduced CD40-induced CD54/ICAM-1 expression, whereas CD40-dependent expression of CD40 and CD95/Fas and four newly defined CD40-responsive genes cIAP2, TRAF1, TRAF4/CART and DR3 were unaffected. Our observations show that the p38 MAPK pathway is required for CD40-induced proliferation and that CD40 induces gene expression via both p38 MAPK-dependent and -independent pathways.
Department of Microbiology, University of Washington, Seattle 98195, USA. andyuk@u.washington.edu
A
A
Craxton
G
G
Shu
J D
JD
Graves
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J
Saklatvala
E G
EG
Krebs
E A
EA
Clark
D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000276:immunology; D001402:B-Lymphocytes / Q000201:enzymology* / Q000276:immunology* / Q000378:metabolism; D019013:CD40 Antigens / Q000096:biosynthesis / Q000276:immunology / Q000502:physiology*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism / Q000502:physiology*; D002455:Cell Division / Q000276:immunology; D004789:Enzyme Activation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000276:immunology*; D015803:HLA-DR3 Antigen / Q000096:biosynthesis; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007075:Immunoglobulin M / Q000276:immunology; D051034:Inhibitor of Apoptosis Proteins; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D047908:Intracellular Signaling Peptides and Proteins; D008213:Lymphocyte Activation / Q000276:immunology; D016393:Lymphoma, B-Cell; D051379:Mice; D020928:Mitogen-Activated Protein Kinases; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000096:biosynthesis; D009687:Nuclear Proteins / Q000096:biosynthesis; D014066:Palatine Tonsil / Q000166:cytology / Q000201:enzymology / Q000276:immunology; D011485:Protein Binding / Q000276:immunology; D014176:Protein Biosynthesis; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011506:Proteins; D011725:Pyridines / Q000494:pharmacology; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism / Q000502:physiology; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D047990:TNF Receptor-Associated Factor 1; D053449:TNF Receptor-Associated Factor 4; D014407:Tumor Cells, Cultured; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; D014764:Viral Proteins / Q000096:biosynthesis; D019014:fas Receptor / Q000096:biosynthesis; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2
D000888:Antibodies, Anti-Idiotypic; D000911:Antibodies, Monoclonal; D019013:CD40 Antigens; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D015803:HLA-DR3 Antigen; D007093:Imidazoles; D007075:Immunoglobulin M; D051034:Inhibitor of Apoptosis Proteins; D018799:Intercellular Adhesion Molecule-1; D047908:Intracellular Signaling Peptides and Proteins; D020928:Mitogen-Activated Protein Kinases; D016328:NF-kappa B; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D011506:Proteins; D011725:Pyridines; D011947:Receptors, Antigen, B-Cell; D018124:Receptors, Tumor Necrosis Factor; D047990:TNF Receptor-Associated Factor 1; D053449:TNF Receptor-Associated Factor 4; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; D014764:Viral Proteins; D019014:fas Receptor; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2; C506367:TRAF4 protein, human; C506368:Traf4 protein, mouse; C044203:anti-IgM; C086430:inhibitor of apoptosis, Nucleopolyhedrovirus; C093642:SB 203580