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,
Departments of
*
Microbiology and
Internal Medicine, University of Iowa, Iowa City, IA 52242; and
Veterans Affairs Medical Center, Iowa City, IA 52242
Signaling through CD40 in B cells leads to B cell proliferation, Ig
and IL-6 secretion, isotype switching, and up-regulation of surface
molecules. TNF receptor-associated factor (TRAF) proteins associate
with the cytoplasmic tail of CD40 and act as adapter molecules. Of the
six TRAFs identified to date, TRAFs 2, 3, 5, and 6 are reported to
associate directly with the cytoplasmic tail of CD40, but previous
studies have principally examined transient overexpression of TRAF6 in
cells that do not normally express CD40. Thus, we examined the role of
TRAF6 in CD40-mediated B lymphocyte effector functions using two
approaches. We produced and stably expressed in mouse B cell lines a
human CD40 molecule with two cytoplasmic domain point mutations
(hCD40EEAA); this mutant fails to bind TRAF6, while showing normal
association with TRAFs 2 and 3. We also inducibly expressed in B cells
a transfected "dominant-negative" TRAF6 molecule which contains
only the C-terminal TRAF-binding domain of TRAF6. Using both molecules,
we found that TRAF6 association with CD40 is important for CD40-induced
IL-6 and Ig secretion, and that TRAF6 mediates its effects on
CD40-stimulated Ig secretion principally through its effects on IL-6
production by the B cell. TRAF6 association with CD40 was also found to
be important for B7-1 up-regulation, but not for up-regulation of other
surface molecules. Interestingly, however, although we could show
TRAF6-dependent CD40-mediated activation of NF-
B in 293 kidney
epithelial cells, no such effect was seen in B cells, suggesting that
TRAF6 has cell-type-specific functions.
This article has been cited by other articles:
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  A. L. Peters, R. M. Plenge, R. R. Graham, D. M. Altshuler, K. L. Moser, P. M. Gaffney, and G. A. Bishop A novel polymorphism of the human CD40 receptor with enhanced function Blood, September 1, 2008; 112(5): 1863 - 1871. [Abstract] [Full Text] [PDF]
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M. E. Munroe and G. A. Bishop A Costimulatory Function for T Cell CD40 J. Immunol., January 15, 2007; 178(2): 671 - 682. [Abstract] [Full Text] [PDF]
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R. M. Andrade, M. Wessendarp, J.-A. C. Portillo, J.-Q. Yang, F. J. Gomez, J. E. Durbin, G. A. Bishop, and C. S. Subauste TNF Receptor-Associated Factor 6-Dependent CD40 Signaling Primes Macrophages to Acquire Antimicrobial Activity in Response to TNF-{alpha} J. Immunol., November 1, 2005; 175(9): 6014 - 6021. [Abstract] [Full Text] [PDF]
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C. R. Moore and G. A. Bishop Differential Regulation of CD40-Mediated TNF Receptor-Associated Factor Degradation in B Lymphocytes J. Immunol., September 15, 2005; 175(6): 3780 - 3789. [Abstract] [Full Text] [PDF]
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L. Mukundan, G. A. Bishop, K. Z. Head, L. Zhang, L. M. Wahl, and J. Suttles TNF Receptor-Associated Factor 6 Is an Essential Mediator of CD40-Activated Proinflammatory Pathways in Monocytes and Macrophages J. Immunol., January 15, 2005; 174(2): 1081 - 1090. [Abstract] [Full Text] [PDF]
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 K. A. Green, C. L. Ahonen, W. J. Cook, and W. R. Green CD40-Associated TRAF 6 Signaling Is Required for Disease Induction in a Retrovirus-Induced Murine Immunodeficiency J. Virol., June 1, 2004; 78(11): 6055 - 6060. [Abstract] [Full Text] [PDF]
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 C. Reyes-Moreno, J. Girouard, R. Lapointe, A. Darveau, and W. Mourad CD40/CD40 Homodimers Are Required for CD40-induced Phosphatidylinositol 3-Kinase-dependent Expression of B7.2 by Human B Lymphocytes J. Biol. Chem., February 27, 2004; 279(9): 7799 - 7806. [Abstract] [Full Text] [PDF]
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S. A. Haxhinasto and G. A. Bishop Synergistic B Cell Activation by CD40 and the B Cell Antigen Receptor: ROLE OF B LYMPHOCYTE ANTIGEN RECEPTOR-MEDIATED KINASE ACTIVATION AND TUMOR NECROSIS FACTOR RECEPTOR-ASSOCIATED FACTOR REGULATION J. Biol. Chem., January 23, 2004; 279(4): 2575 - 2582. [Abstract] [Full Text] [PDF]
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B. S. Hostager, S. A. Haxhinasto, S. L. Rowland, and G. A. Bishop Tumor Necrosis Factor Receptor-associated Factor 2 (TRAF2)-deficient B Lymphocytes Reveal Novel Roles for TRAF2 in CD40 Signaling J. Biol. Chem., November 14, 2003; 278(46): 45382 - 45390. [Abstract] [Full Text] [PDF]
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S.-J. Yeo, J.-G. Yoon, and A.-K. Yi Myeloid Differentiation Factor 88-dependent Post-transcriptional Regulation of Cyclooxygenase-2 Expression by CpG DNA: TUMOR NECROSIS FACTOR-{alpha} RECEPTOR-ASSOCIATED FACTOR 6, A DIVERGING POINT IN THE Toll-LIKE RECEPTOR 9-SIGNALING J. Biol. Chem., October 17, 2003; 278(42): 40590 - 40600. [Abstract] [Full Text] [PDF]
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M. Baccam, S.-Y. Woo, C. Vinson, and G. A. Bishop CD40-Mediated Transcriptional Regulation of the IL-6 Gene in B Lymphocytes: Involvement of NF-{kappa}B, AP-1, and C/EBP J. Immunol., March 15, 2003; 170(6): 3099 - 3108. [Abstract] [Full Text] [PDF]
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S. M. Propst, K. Estell, and L. M. Schwiebert CD40-mediated Activation of NF-kappa B in Airway Epithelial Cells J. Biol. Chem., September 27, 2002; 277(40): 37054 - 37063. [Abstract] [Full Text] [PDF]
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C. Hull, G. McLean, F. Wong, P. J. Duriez, and A. Karsan Lipopolysaccharide Signals an Endothelial Apoptosis Pathway Through TNF Receptor-Associated Factor 6-Mediated Activation of c-Jun NH2-Terminal Kinase J. Immunol., September 1, 2002; 169(5): 2611 - 2618. [Abstract] [Full Text] [PDF]
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S. A. Haxhinasto, B. S. Hostager, and G. A. Bishop Cutting Edge: Molecular Mechanisms of Synergy Between CD40 and the B Cell Antigen Receptor: Role for TNF Receptor-Associated Factor 2 in Receptor Interaction J. Immunol., August 1, 2002; 169(3): 1145 - 1149. [Abstract] [Full Text] [PDF]
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 G. A. Bishop, B. S. Hostager, and K. D. Brown Mechanisms of TNF receptor-associated factor (TRAF) regulation in B lymphocytes J. Leukoc. Biol., July 1, 2002; 72(1): 19 - 23. [Abstract] [Full Text] [PDF]
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K. D. Brown, B. S. Hostager, and G. A. Bishop Regulation of TRAF2 Signaling by Self-induced Degradation J. Biol. Chem., May 24, 2002; 277(22): 19433 - 19438. [Abstract] [Full Text] [PDF]
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J. Mann, F. Oakley, P. W. M. Johnson, and D. A. Mann CD40 Induces Interleukin-6 Gene Transcription in Dendritic Cells. REGULATION BY TRAF2, AP-1, NF-kappa B, AND CBF1 J. Biol. Chem., May 3, 2002; 277(19): 17125 - 17138. [Abstract] [Full Text] [PDF]
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 T. Yasui, M. Muraoka, Y. Takaoka-Shichijo, I. Ishida, N. Takegahara, J. Uchida, A. Kumanogoh, S. Suematsu, M. Suzuki, and H. Kikutani Dissection of B cell differentiation during primary immune responses in mice with altered CD40 signals Int. Immunol., March 1, 2002; 14(3): 319 - 329. [Abstract] [Full Text] [PDF]
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L. K. Busch and G. A. Bishop Multiple Carboxyl-Terminal Regions of the EBV Oncoprotein, Latent Membrane Protein 1, Cooperatively Regulate Signaling to B Lymphocytes Via TNF Receptor-Associated Factor (TRAF)-Dependent and TRAF-Independent Mechanisms J. Immunol., November 15, 2001; 167(10): 5805 - 5813. [Abstract] [Full Text] [PDF]
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 K. D. Brown, B. S. Hostager, and G. A. Bishop Differential Signaling and Tumor Necrosis Factor Receptor-Associated Factor (Traf) Degradation Mediated by Cd40 and the Epstein-Barr Virus Oncoprotein Latent Membrane Protein 1 (Lmp1) J. Exp. Med., April 16, 2001; 193(8): 943 - 954. [Abstract] [Full Text] [PDF]
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G. A. Bishop, Y. Hsing, B. S. Hostager, S. V. Jalukar, L. M. Ramirez, and M. A. Tomai Molecular Mechanisms of B Lymphocyte Activation by the Immune Response Modifier R-848 J. Immunol., November 15, 2000; 165(10): 5552 - 5557. [Abstract] [Full Text] [PDF]
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