Abstract
IL-2 stimulates extracellular signal-regulated protein kinase (ERK) and p38 mitogen-activated protein kinase (MAPK) in various immune cell populations. The functional roles that these kinases play are still unclear. In this study, we examined whether MAPK kinase (MKK)/ERK and p38 MAPK pathways are necessary for IL-2 to activate NK cells. Using freshly isolated human NK cells, we established that an intact MKK/ERK pathway is necessary for IL-2 to activate NK cells to express at least four known biological responses: LAK generation, IFN-gamma secretion, and CD25 and CD69 expression. IL-2 induced ERK activation within 5 min. Treatment of NK cells with a specific inhibitor of MKK1/2, PD98059, during the IL-2 stimulation blocked in a dose-dependent manner each of four sequelae, with inhibition of lymphokine-activated killing induction being least sensitive to MKK/ERK pathway blockade. Activation of p38 MAPK by IL-2 was not detected in NK cells. In contrast to what was observed by others in T lymphocytes, SB203850, a specific inhibitor of p38 MAPK, did not inhibit IL-2-activated NK functions. This data indicate that p38 MAPK activation was not required for IL-2 to activate NK cells for the four functions examined. These results reveal selective signaling differences between NK cells and T lymphocytes; in NK cells, the MKK/ERK pathway and not p38 MAPK plays a critical positive regulatory role during activation by IL-2.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Antigens, CD / biosynthesis
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Antigens, Differentiation, T-Lymphocyte / biosynthesis
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Biomarkers
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Enzyme Activation / immunology
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Enzyme Inhibitors / pharmacology
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Humans
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Imidazoles / pharmacology
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Interferon-gamma / metabolism
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Interleukin-2 / immunology*
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Killer Cells, Lymphokine-Activated / enzymology
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Killer Cells, Lymphokine-Activated / immunology
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Killer Cells, Natural / enzymology*
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Killer Cells, Natural / immunology*
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Killer Cells, Natural / metabolism
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Lectins, C-Type
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Lymphocyte Activation / immunology*
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MAP Kinase Kinase 1
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MAP Kinase Kinase 2
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MAP Kinase Signaling System / immunology*
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Mitogen-Activated Protein Kinase Kinases / metabolism
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Mitogen-Activated Protein Kinase Kinases / physiology
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Mitogen-Activated Protein Kinases / antagonists & inhibitors
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Mitogen-Activated Protein Kinases / metabolism
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Mitogen-Activated Protein Kinases / physiology
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Protein Serine-Threonine Kinases / metabolism
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Protein Serine-Threonine Kinases / physiology
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Protein-Tyrosine Kinases / metabolism
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Protein-Tyrosine Kinases / physiology
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Pyridines / pharmacology
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Receptors, Interleukin-2 / biosynthesis
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p38 Mitogen-Activated Protein Kinases
Substances
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Antigens, CD
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Antigens, Differentiation, T-Lymphocyte
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Biomarkers
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CD69 antigen
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Enzyme Inhibitors
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Imidazoles
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Interleukin-2
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Lectins, C-Type
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Pyridines
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Receptors, Interleukin-2
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Interferon-gamma
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MAP2K2 protein, human
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Protein-Tyrosine Kinases
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Protein Serine-Threonine Kinases
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Mitogen-Activated Protein Kinases
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p38 Mitogen-Activated Protein Kinases
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MAP Kinase Kinase 1
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MAP Kinase Kinase 2
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MAP2K1 protein, human
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Mitogen-Activated Protein Kinase Kinases
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SB 203580