Abstract
Interleukin 15 (IL-15) promotes the survival of natural killer (NK) cells by preventing apoptosis through mechanisms unknown at present. Here we identify Bim, Noxa and Mcl-1 as key regulators of IL-15-dependent survival of NK cells. IL-15 suppressed apoptosis by limiting Bim expression through the kinases Erk1 and Erk2 and mechanisms dependent on the transcription factor Foxo3a, while promoting expression of Mcl-1, which was necessary and sufficient for the survival of NK cells. Withdrawal of IL-15 led to upregulation of Bim and, accordingly, both Bim-deficient and Foxo3a-/- NK cells were resistant to cytokine deprivation. Finally, IL-15-mediated inactivation of Foxo3a and cell survival were dependent on phosphotidylinositol-3-OH kinase. Thus, IL-15 regulates the survival of NK cells at multiple steps, with Bim and Noxa being key antagonists of Mcl-1, the critical survivor factor in this process.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / immunology*
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Apoptosis Regulatory Proteins / immunology
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Apoptosis Regulatory Proteins / metabolism*
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Bcl-2-Like Protein 11
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Cell Survival / immunology
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Flow Cytometry
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Forkhead Box Protein O3
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Forkhead Transcription Factors / immunology
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Forkhead Transcription Factors / metabolism
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Immunoblotting
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Interleukin-15 / immunology
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Interleukin-15 / metabolism*
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Killer Cells, Natural / immunology
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Killer Cells, Natural / metabolism*
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Membrane Proteins / immunology
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Membrane Proteins / metabolism*
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Mice
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Mitogen-Activated Protein Kinase 3 / immunology
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Mitogen-Activated Protein Kinase 3 / metabolism
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Myeloid Cell Leukemia Sequence 1 Protein
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Neoplasm Proteins / immunology
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Neoplasm Proteins / metabolism*
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Phosphatidylinositol 3-Kinases / immunology
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Phosphatidylinositol 3-Kinases / metabolism
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Polymerase Chain Reaction
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Proto-Oncogene Proteins / immunology
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins c-bcl-2 / immunology
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Proto-Oncogene Proteins c-bcl-2 / metabolism*
Substances
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Apoptosis Regulatory Proteins
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Bcl-2-Like Protein 11
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Bcl2l11 protein, mouse
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Forkhead Box Protein O3
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Forkhead Transcription Factors
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FoxO3 protein, mouse
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Interleukin-15
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Mcl1 protein, mouse
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Membrane Proteins
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Myeloid Cell Leukemia Sequence 1 Protein
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Neoplasm Proteins
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Pmaip1 protein, mouse
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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Phosphatidylinositol 3-Kinases
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Mitogen-Activated Protein Kinase 3