Abstract
PIM kinases are a family of three serine/threonine kinases expressed following T cell activation. Using potent selective small molecule antagonists of PIM-1/3 kinases, we demonstrate a potential role for these enzymes in naïve and effector CD4+ T cell activation. PIM-1/3 inhibition prevented CD4+ T cell proliferation by inducing a G0/G1 cell cycle arrest without affecting cellular survival. In the absence of PIM-1/3 kinase activity, naïve CD4+ T cells failed to fully differentiate into effector cells both in vitro and in vivo. Therapeutic dosing of a PIM-1/3 inhibitor was efficacious in a CD4+ T cell-mediated model of inflammatory bowel disease suggesting that PIM-1 and PIM-3 kinase activity contributes to sustained disease severity. These results demonstrate that PIM-1/3 kinases have an important role in CD4+ T cell responses and inhibition of this activity may provide a therapeutic benefit in T cell-mediated diseases.
Copyright © 2011 Elsevier Inc. All rights reserved.
MeSH terms
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Animals
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Apoptosis / drug effects
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CD4-Positive T-Lymphocytes / drug effects
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CD4-Positive T-Lymphocytes / enzymology*
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CD4-Positive T-Lymphocytes / immunology
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Cell Cycle Checkpoints / drug effects
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Cell Differentiation / drug effects
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Cell Growth Processes / drug effects
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Cell Growth Processes / genetics
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Cell Growth Processes / immunology
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Cell Survival / drug effects
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Cytokines / biosynthesis
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G1 Phase / drug effects
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Humans
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Inflammatory Bowel Diseases / drug therapy
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Inflammatory Bowel Diseases / enzymology*
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Inflammatory Bowel Diseases / genetics
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Inflammatory Bowel Diseases / immunology
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Janus Kinases / metabolism
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Lymphocyte Activation
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MAP Kinase Kinase Kinases / metabolism
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Mice, SCID
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Protein Kinase Inhibitors / pharmacology
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Proto-Oncogene Proteins c-pim-1 / antagonists & inhibitors
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Proto-Oncogene Proteins c-pim-1 / genetics
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Proto-Oncogene Proteins c-pim-1 / immunology*
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Proto-Oncogene Proteins c-pim-1 / metabolism*
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Resting Phase, Cell Cycle / drug effects
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Signal Transduction / drug effects
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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Cytokines
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Protein Kinase Inhibitors
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Janus Kinases
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Proto-Oncogene Proteins c-pim-1
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proto-oncogene proteins pim
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p38 Mitogen-Activated Protein Kinases
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MAP Kinase Kinase Kinases