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Departments of
*
Microbiology and
Pharmacology, University of Washington, Seattle, WA 98195; and
The Kennedy Institute of Rheumatology, London, United Kingdom
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-
B 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-B elements, indicating a requirement for the p38
MAPK pathway in CD40-induced NF-B activation. However, CD40-mediated
NF-B binding was not affected by SB203580, suggesting that NF-B
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.
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B. G. Werneburg, S. J. Zoog, T. T. A. Dang, M. R. Kehry, and J. J. Crute Molecular Characterization of CD40 Signaling Intermediates J. Biol. Chem., November 9, 2001; 276(46): 43334 - 43342. [Abstract] [Full Text] [PDF]
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J. Varghese, S. Chattopadhaya, and A. Sarin Inhibition of p38 Kinase Reveals a TNF-{{alpha}}-Mediated, Caspase-Dependent, Apoptotic Death Pathway in a Human Myelomonocyte Cell Line J. Immunol., June 1, 2001; 166(11): 6570 - 6577. [Abstract] [Full Text] [PDF]
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K. M. Ardeshna, A. R. Pizzey, S. Devereux, and A. Khwaja The PI3 kinase, p38 SAP kinase, and NF-kappa B signal transduction pathways are involved in the survival and maturation of lipopolysaccharide-stimulated human monocyte-derived dendritic cells Blood, August 1, 2000; 96(3): 1039 - 1046. [Abstract] [Full Text] [PDF]
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S. Hippenstiel, S. Soeth, B. Kellas, O. Fuhrmann, J. Seybold, M. Krull, C. v. Eichel-Streiber, M. Goebeler, S. Ludwig, and N. Suttorp Rho proteins and the p38-MAPK pathway are important mediators for LPS-induced interleukin-8 expression in human endothelial cells Blood, May 15, 2000; 95(10): 3044 - 3051. [Abstract] [Full Text] [PDF]
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J. M. Swart, D. M. Bergeron, and T. C. Chiles Identification of a Membrane Ig-Induced p38 Mitogen-Activated Protein Kinase Module That Regulates cAMP Response Element Binding Protein Phosphorylation and Transcriptional Activation in CH31 B Cell Lymphomas J. Immunol., March 1, 2000; 164(5): 2311 - 2319. [Abstract] [Full Text] [PDF]
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E. W.-F. Lam, J. Glassford, L. Banerji, N. S. B. Thomas, P. Sicinski, and G. G. B. Klaus Cyclin D3 Compensates for Loss of Cyclin D2 in Mouse B-lymphocytes Activated via the Antigen Receptor and CD40 J. Biol. Chem., February 4, 2000; 275(5): 3479 - 3484. [Abstract] [Full Text] [PDF]
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A. Aicher, G. L. Shu, D. Magaletti, T. Mulvania, A. Pezzutto, A. Craxton, and E. A. Clark Differential Role for p38 Mitogen-Activated Protein Kinase in Regulating CD40-Induced Gene Expression in Dendritic Cells and B Cells J. Immunol., December 1, 1999; 163(11): 5786 - 5795. [Abstract] [Full Text] [PDF]
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 G. Hartmann, G. J. Weiner, and A. M. Krieg CpG DNA: A potent signal for growth, activation, and maturation of human dendritic cells PNAS, August 3, 1999; 96(16): 9305 - 9310. [Abstract] [Full Text] [PDF]
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 M. R. Posner, L. A. Cavacini, M. P. Upton, K. C. Tillman, E. R. Gornstein, and C. M. Norris Jr. Surface Membrane-expressed CD40 Is Present on Tumor Cells from Squamous Cell Cancer of the Head and Neck in Vitro and in Vivo and Regulates Cell Growth in Tumor Cell Lines Clin. Cancer Res., August 1, 1999; 5(8): 2261 - 2270. [Abstract] [Full Text] [PDF]
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M. Rolli, A. Kotlyarov, K. M. Sakamoto, M. Gaestel, and A. Neininger Stress-induced Stimulation of Early Growth Response Gene-1 by p38/Stress-activated Protein Kinase 2 Is Mediated by a cAMP-responsive Promoter Element in a MAPKAP Kinase 2-independent Manner J. Biol. Chem., July 9, 1999; 274(28): 19559 - 19564. [Abstract] [Full Text] [PDF]
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A. G. Eliopoulos, N. J. Gallagher, S. M. S. Blake, C. W. Dawson, and L. S. Young Activation of the p38 Mitogen-activated Protein Kinase Pathway by Epstein-Barr Virus-encoded Latent Membrane Protein 1 Coregulates Interleukin-6 and Interleukin-8 Production J. Biol. Chem., June 4, 1999; 274(23): 16085 - 16096. [Abstract] [Full Text] [PDF]
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 H. Nakamura, A. Kawakami, S. Yamasaki, Y. Kawabe, T. Nakamura, and K. Eguchi Expression of mitogen activated protein kinases in labial salivary glands of patients with Sjogren's syndrome Ann Rheum Dis, June 1, 1999; 58(6): 382 - 385. [Abstract] [Full Text]
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S. S. Pullen, T. T. A. Dang, J. J. Crute, and M. R. Kehry CD40 Signaling through Tumor Necrosis Factor Receptor-associated Factors (TRAFs). BINDING SITE SPECIFICITY AND ACTIVATION OF DOWNSTREAM PATHWAYS BY DISTINCT TRAFs J. Biol. Chem., May 14, 1999; 274(20): 14246 - 14254. [Abstract] [Full Text] [PDF]
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S.-Y. Hong, W.-H. Yoon, J.-H. Park, S.-G. Kang, J.-H. Ahn, and T. H. Lee Involvement of Two NF-kappa B Binding Elements in Tumor Necrosis Factor alpha -, CD40-, and Epstein-Barr Virus Latent Membrane Protein 1-mediated Induction of the Cellular Inhibitor of Apoptosis Protein 2 Gene J. Biol. Chem., June 9, 2000; 275(24): 18022 - 18028. [Abstract] [Full Text] [PDF]
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R. Y. Liu, C. Fan, G. Liu, N. E. Olashaw, and K. S. Zuckerman Activation of p38 Mitogen-activated Protein Kinase Is Required for Tumor Necrosis Factor-alpha -supported Proliferation of Leukemia and Lymphoma Cell Lines J. Biol. Chem., July 7, 2000; 275(28): 21086 - 21093. [Abstract] [Full Text] [PDF]
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M. M. Awad, H. Enslen, J. M. Boylan, R. J. Davis, and P. A. Gruppuso Growth Regulation via p38 Mitogen-activated Protein Kinase in Developing Liver J. Biol. Chem., December 1, 2000; 275(49): 38716 - 38721. [Abstract] [Full Text] [PDF]
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Y. Arimura, M. Ogimoto, K. Mitomo, T. Katagiri, K.-i. Yamamoto, S. Volarevic, K. Mizuno, and H. Yakura CD45 Is Required for CD40-induced Inhibition of DNA Synthesis and Regulation of c-Jun NH2-terminal Kinase and p38 in BAL-17 B Cells J. Biol. Chem., March 9, 2001; 276(11): 8550 - 8556. [Abstract] [Full Text] [PDF]
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Y. Abe, S. Matsumoto, K. Kito, and N. Ueda Cloning and Expression of a Novel MAPKK-like Protein Kinase, Lymphokine-activated Killer T-cell-originated Protein Kinase, Specifically Expressed in the Testis and Activated Lymphoid Cells J. Biol. Chem., July 7, 2000; 275(28): 21525 - 21531. [Abstract] [Full Text] [PDF]
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 H. Li and E. P. Nord CD40 ligation stimulates MCP-1 and IL-8 production, TRAF6 recruitment, and MAPK activation in proximal tubule cells Am J Physiol Renal Physiol, June 1, 2002; 282(6): F1020 - F1033. [Abstract] [Full Text] [PDF]
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