Abstract
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.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Antibodies, Anti-Idiotypic / pharmacology
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Antibodies, Monoclonal / pharmacology
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Apoptosis / immunology
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B-Lymphocytes / enzymology*
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B-Lymphocytes / immunology*
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B-Lymphocytes / metabolism
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CD40 Antigens / biosynthesis
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CD40 Antigens / immunology
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CD40 Antigens / physiology*
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Calcium-Calmodulin-Dependent Protein Kinases / metabolism
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Calcium-Calmodulin-Dependent Protein Kinases / physiology*
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Cell Division / immunology
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Enzyme Activation / drug effects
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Gene Expression Regulation / immunology*
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HLA-DR3 Antigen / biosynthesis
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Humans
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Imidazoles / pharmacology
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Immunoglobulin M / immunology
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Inhibitor of Apoptosis Proteins
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Intercellular Adhesion Molecule-1 / biosynthesis
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Intracellular Signaling Peptides and Proteins
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Lymphocyte Activation* / immunology
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Lymphoma, B-Cell
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Mice
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Mitogen-Activated Protein Kinases*
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NF-kappa B / genetics
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NF-kappa B / metabolism
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Neoplasm Proteins / biosynthesis
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Nuclear Proteins / biosynthesis
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Palatine Tonsil / cytology
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Palatine Tonsil / enzymology
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Palatine Tonsil / immunology
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Protein Binding / immunology
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Protein Biosynthesis
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Protein Serine-Threonine Kinases / metabolism
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Proteins*
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Pyridines / pharmacology
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Receptors, Antigen, B-Cell / metabolism
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Receptors, Antigen, B-Cell / physiology
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Receptors, Tumor Necrosis Factor / metabolism
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TNF Receptor-Associated Factor 1
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TNF Receptor-Associated Factor 4
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Tumor Cells, Cultured
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Tumor Necrosis Factor Receptor-Associated Peptides and Proteins
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Viral Proteins / biosynthesis
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fas Receptor / biosynthesis
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p38 Mitogen-Activated Protein Kinases
Substances
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Antibodies, Anti-Idiotypic
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Antibodies, Monoclonal
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CD40 Antigens
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HLA-DR3 Antigen
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Imidazoles
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Immunoglobulin M
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Inhibitor of Apoptosis Proteins
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Intracellular Signaling Peptides and Proteins
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NF-kappa B
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Neoplasm Proteins
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Nuclear Proteins
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Proteins
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Pyridines
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Receptors, Antigen, B-Cell
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Receptors, Tumor Necrosis Factor
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TNF Receptor-Associated Factor 1
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TNF Receptor-Associated Factor 4
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TRAF4 protein, human
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Traf4 protein, mouse
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Tumor Necrosis Factor Receptor-Associated Peptides and Proteins
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Viral Proteins
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anti-IgM
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fas Receptor
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inhibitor of apoptosis, Nucleopolyhedrovirus
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Intercellular Adhesion Molecule-1
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MAP-kinase-activated kinase 2
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Protein Serine-Threonine Kinases
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Calcium-Calmodulin-Dependent Protein Kinases
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Mitogen-Activated Protein Kinases
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p38 Mitogen-Activated Protein Kinases
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SB 203580