Abstract
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-gamma 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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Activating Transcription Factor 2
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Animals
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CD28 Antigens / immunology*
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CD3 Complex / immunology
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CD3 Complex / metabolism
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Calcium / physiology
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Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
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Cell Nucleus / drug effects
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Cell Nucleus / enzymology
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Cell Nucleus / metabolism
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Cells, Cultured
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Cyclic AMP Response Element-Binding Protein / antagonists & inhibitors
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Cyclic AMP Response Element-Binding Protein / biosynthesis
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Cytokines / antagonists & inhibitors
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Cytokines / metabolism
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Drug Synergism
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Enzyme Activation
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Humans
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Imidazoles / pharmacology
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JNK Mitogen-Activated Protein Kinases
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Jurkat Cells
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Lymphocyte Activation* / drug effects
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Mitogen-Activated Protein Kinases*
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Proto-Oncogene Proteins c-jun / antagonists & inhibitors
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Proto-Oncogene Proteins c-jun / biosynthesis
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Pyridines / pharmacology
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Receptors, Antigen, T-Cell / immunology*
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Signal Transduction / drug effects
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Signal Transduction / immunology*
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T-Lymphocytes / drug effects
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T-Lymphocytes / enzymology*
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T-Lymphocytes / immunology*
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T-Lymphocytes / metabolism
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Transcription Factors / antagonists & inhibitors
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Transcription Factors / biosynthesis
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p38 Mitogen-Activated Protein Kinases
Substances
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ATF2 protein, human
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Activating Transcription Factor 2
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Atf2 protein, mouse
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CD28 Antigens
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CD3 Complex
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Cyclic AMP Response Element-Binding Protein
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Cytokines
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Imidazoles
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Proto-Oncogene Proteins c-jun
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Pyridines
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Receptors, Antigen, T-Cell
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Transcription Factors
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Calcium-Calmodulin-Dependent Protein Kinases
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JNK Mitogen-Activated 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
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Calcium