JNK is involved in signal integration during costimulation of T lymphocytes.
T lymphocyte activation and interleukin-2 (IL-2) production require at least two signals, generated by phorbol ester (TPA) and Ca2+ ionophore or costimulation of the T cell receptor (TCR) and the CD28 auxiliary receptor. We investigated how these stimuli affect mitogen activated protein (MAP) kinases. Full activation of the MAP kinases that phosphorylate the Jun activation domain, JNK1 and JNK2, required costimulation of T cells with either TPA and Ca2+ ionophore or antibodies to TCR and CD28. Alone, each stimulus resulted in little or no activation. Similar to its effect on IL-2 induction, cyclosporin A (CsA) inhibited the synergistic activation of JNK, and a competitive inhibitor of Jun phosphorylation by JNK inhibited IL-2 promoter activation. By contrast, the MAP kinases ERK1 and ERK2 were fully activated by TPA or TCR stimulation and were not affected by Ca2+, CD28, or CsA. Hence, integration of signals that lead to T cell activation occurs at the level of JNK activation.
Su
B
B
Department of Pharmacology, School of Medicine, University of California, San Diego, La Jolla 92093-0636.
Jacinto
E
E
Hibi
M
M
Kallunki
T
T
Karin
M
M
Ben-Neriah
Y
Y
D000818:Animals; D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002460:Cell Line; D016572:Cyclosporine / Q000494:pharmacology; D004789:Enzyme Activation; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D008213:Lymphocyte Activation; D051379:Mice; D020928:Mitogen-Activated Protein Kinases; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D016755:Proto-Oncogene Proteins c-jun; D000001:Calcimycin; D016572:Cyclosporine; D017346:Protein Serine-Threonine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium