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,
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Autoimmunity/Diabetes Group, John P. Robarts Research Institute, London, Ontario, Canada; and Departments of
Microbiology and Immunology and
Medicine, University of Western Ontario, London, Ontario, Canada
Optimal T cell activation requires two signals, one generated by
TCR and another by the CD28 costimulatory receptor. In this study, we
investigated the regulation of costimulation-induced mitogen-activated
protein kinase (MAPK) activation in primary mouse T cells. In contrast
to that reported for human Jurkat T cells, we found that p38 MAPK, but
not Jun NH2-terminal kinase (JNK), is weakly activated upon
stimulation with either anti-CD3 or anti-CD28 in murine
thymocytes and splenic T cells. However, p38 MAPK is activated strongly
and synergistically by either CD3/CD28 coligation or
PMA/Ca2+ ionophore stimulation, which mimics
TCR-CD3/CD28-mediated signaling. Activation of p38 MAPK correlates
closely with the stimulation of T cell proliferation. In contrast,
PMA-induced JNK activation is inhibited by Ca2+ ionophore.
T cell proliferation and production of IL-2, IL-4, and IFN-
induced
by both CD3 and CD3/CD28 ligation and the nuclear expression of the
c-Jun and ATF-2 proteins are each blocked by the p38 MAPK inhibitor
SB203580. Our findings demonstrate that p38 MAPK 1) plays an important
role in signal integration during costimulation of primary mouse T
cells, 2) may be involved in the induction of c-Jun activation and
augmentation of AP-1 transcriptional activity, and 3) regulates whether
T cells enter a state of functional
unresponsiveness.
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Z. Guo, G. Clydesdale, J. Cheng, K. Kim, L. Gan, D. J. McConkey, S. E. Ullrich, Y. Zhuang, and B. Su Disruption of Mekk2 in Mice Reveals an Unexpected Role for MEKK2 in Modulating T-Cell Receptor Signal Transduction Mol. Cell. Biol., August 15, 2002; 22(16): 5761 - 5768. [Abstract] [Full Text] [PDF]
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W. Li, C. D. Whaley, J. L. Bonnevier, A. Mondino, M. E. Martin, K. M. Aagaard-Tillery, and D. L. Mueller CD28 Signaling Augments Elk-1-Dependent Transcription at the c-fos Gene During Antigen Stimulation J. Immunol., July 15, 2001; 167(2): 827 - 835. [Abstract] [Full Text] [PDF]
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V. Lafont, J. Liautard, J. P. Liautard, and J. Favero Production of TNF-{{alpha}} by Human V{{gamma}}9V{{delta}}2 T Cells Via Engagement of Fc{{gamma}}RIIIA, the Low Affinity Type 3 Receptor for the Fc Portion of IgG, Expressed upon TCR Activation by Nonpeptidic Antigen J. Immunol., June 15, 2001; 166(12): 7190 - 7199. [Abstract] [Full Text] [PDF]
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A. Skapenko, P. E. Lipsky, H.-G. Kraetsch, J. R. Kalden, and H. Schulze-Koops Antigen-Independent Th2 Cell Differentiation by Stimulation of CD28: Regulation Via IL-4 Gene Expression and Mitogen-Activated Protein Kinase Activation J. Immunol., April 1, 2001; 166(7): 4283 - 4292. [Abstract] [Full Text] [PDF]
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J. Zhang, K. V. Salojin, and T. L. Delovitch CD28 co-stimulation restores T cell responsiveness in NOD mice by overcoming deficiencies in Rac-1/p38 mitogen-activated protein kinase signaling and IL-2 and IL-4 gene transcription Int. Immunol., March 1, 2001; 13(3): 377 - 384. [Abstract] [Full Text] [PDF]
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A. M. Reimold, J. Kim, R. Finberg, and L. H. Glimcher Decreased immediate inflammatory gene induction in activating transcription factor-2 mutant mice Int. Immunol., February 1, 2001; 13(2): 241 - 248. [Abstract] [Full Text] [PDF]
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C. Pasare, P. Mukherjee, A. Verhoef, P. Bansal, S. K. Mendiratta, A. George, J. R. Lamb, S. Rath, and V. Bal T cells in mice expressing a transgenic human TCR{beta} chain get positively selected but cannot be activated in the periphery by signaling through TCR Int. Immunol., January 1, 2001; 13(1): 53 - 62. [Abstract] [Full Text] [PDF]
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C.-T. Yu, H.-m. Shih, and M.-Z. Lai Multiple Signals Required for Cyclic AMP-Responsive Element Binding Protein (CREB) Binding Protein Interaction Induced by CD3/CD28 Costimulation J. Immunol., January 1, 2001; 166(1): 284 - 292. [Abstract] [Full Text] [PDF]
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J. L. Cannons, Y. Choi, and T. H. Watts Role of TNF Receptor-Associated Factor 2 and p38 Mitogen-Activated Protein Kinase Activation During 4-1BB-Dependent Immune Response J. Immunol., December 1, 2000; 165(11): 6193 - 6204. [Abstract] [Full Text] [PDF]
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C.-H. Chen, D.-H. Zhang, J. M. LaPorte, and A. Ray Cyclic AMP Activates p38 Mitogen-Activated Protein Kinase in Th2 Cells: Phosphorylation of GATA-3 and Stimulation of Th2 Cytokine Gene Expression J. Immunol., November 15, 2000; 165(10): 5597 - 5605. [Abstract] [Full Text] [PDF]
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M. Ishaq, M. Fan, and V. Natarajan Accumulation of RXR{alpha} During Activation of Cycling Human T Lymphocytes: Modulation of RXRE Transactivation Function by Mitogen-Activated Protein Kinase Pathways J. Immunol., October 15, 2000; 165(8): 4217 - 4225. [Abstract] [Full Text] [PDF]
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 W. MIKULITS, B. PRADET-BALADE, B. HABERMANN, H. BEUG, J. A. GARCIA-SANZ, and E. W. MÜLLNER Isolation of translationally controlled mRNAs by differential screening FASEB J, August 1, 2000; 14(11): 1641 - 1652. [Abstract] [Full Text]
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S. Zhang and M. H. Kaplan The p38 Mitogen-Activated Protein Kinase Is Required for IL-12-Induced IFN-{gamma} Expression J. Immunol., August 1, 2000; 165(3): 1374 - 1380. [Abstract] [Full Text] [PDF]
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T.-K. Yu, E. G. Caudell, C. Smid, and E. A. Grimm IL-2 Activation of NK Cells: Involvement of MKK1/2/ERK But Not p38 Kinase Pathway J. Immunol., June 15, 2000; 164(12): 6244 - 6251. [Abstract] [Full Text] [PDF]
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P. G. del Arco, S. Martinez-Martinez, J. L. Maldonado, I. Ortega-Perez, and J. M. Redondo A Role for the p38 MAP Kinase Pathway in the Nuclear Shuttling of NFATp J. Biol. Chem., April 28, 2000; 275(18): 13872 - 13878. [Abstract] [Full Text] [PDF]
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J. Zhang, J.-X. Gao, K. Salojin, Q. Shao, M. Grattan, C. Meagher, D. W. Laird, and T. L. Delovitch Regulation of FAS Ligand Expression during Activation-Induced Cell Death in T Cells by p38 Mitogen-Activated Protein Kinase and C-Jun Nh2-Terminal Kinase J. Exp. Med., March 20, 2000; 191(6): 1017 - 1030. [Abstract] [Full Text] [PDF]
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F. V. Lali, A. E. Hunt, S. J. Turner, and B. M. J. Foxwell The Pyridinyl Imidazole Inhibitor SB203580 Blocks Phosphoinositide-dependent Protein Kinase Activity, Protein Kinase B Phosphorylation, and Retinoblastoma Hyperphosphorylation in Interleukin-2-stimulated T Cells Independently of p38 Mitogen-activated Protein Kinase J. Biol. Chem., March 15, 2000; 275(10): 7395 - 7402. [Abstract] [Full Text] [PDF]
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U. Bommhardt, Y. Scheuring, C. Bickel, R. Zamoyska, and T. Hunig MEK Activity Regulates Negative Selection of Immature CD4+CD8+ Thymocytes J. Immunol., March 1, 2000; 164(5): 2326 - 2337. [Abstract] [Full Text] [PDF]
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K. V. Salojin, J. Zhang, C. Meagher, and T. L. Delovitch ZAP-70 Is Essential for the T Cell Antigen Receptor-induced Plasma Membrane Targeting of SOS and Vav in T Cells J. Biol. Chem., February 25, 2000; 275(8): 5966 - 5975. [Abstract] [Full Text] [PDF]
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E. Fernandez Thymocyte development past the CD4+CD8+ stage requires an active p38 mitogen-activated protein kinase Blood, February 15, 2000; 95(4): 1356 - 1361. [Abstract] [Full Text] [PDF]
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S.-C. Hsu, M. A. Gavrilin, M.-H. Tsai, J. Han, and M.-Z. Lai p38 Mitogen-activated Protein Kinase Is Involved in Fas Ligand Expression J. Biol. Chem., September 3, 1999; 274(36): 25769 - 25776. [Abstract] [Full Text] [PDF]
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T. A. Fischer, A. Palmetshofer, S. Gambaryan, E. Butt, C. Jassoy, U. Walter, S. Sopper, and S. M. Lohmann Activation of cGMP-dependent Protein Kinase Ibeta Inhibits Interleukin 2 Release and Proliferation of T Cell Receptor-stimulated Human Peripheral T Cells J. Biol. Chem., February 16, 2001; 276(8): 5967 - 5974. [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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