Abstract
Mitogen-activated protein kinase phosphatase-1 (MKP-1), also known as dual specificity phosphatase-1 (DUSP-1), plays a crucial role in the deactivation of MAPKs. Several drugs with immune-suppressive properties modulate MKP-1 expression as part of their mechanism of action. We investigated the effect of mTOR inhibition through rapamycin and a dual mTOR inhibitor (AZD2014) on MKP-1 expression. Low dose rapamycin led to a rapid activation of both AKT and ERK pathways with a subsequent increase in MKP-1 expression. Rapamycin treatment led to phosphorylation of CREB, transcription factor 1 (ATF1), and ATF2, three transcription factors that bind to the cyclic AMP-responsive elements on the Mkp-1 promoter. Inhibition of either the MEK/ERK or the AKT pathway attenuated rapamycin-mediated MKP-1 induction. AZD2014 did not activate AKT but activated the ERK pathway, leading to a moderate MKP-1 induction. Using bone marrow-derived macrophages (BMDMs) derived from wild-type (WT) mice or mice deficient in AKT1 and AKT2 isoforms or BMDM from targeted deficiency in MEK1 and MEK2, we show that rapamycin treatment led to an increased MKP1 expression in BMDM from WT but failed to do so in BMDMs lacking the AKT1 isoform or MEK1 and MEK2. Importantly, rapamycin pretreatment inhibited LPS-mediated p38 activation and decreased nitric oxide and IL-6 production. Our work provides a conceptual framework for the observed immune modulatory effect of mTOR inhibition.
Keywords:
Akt PKB; Dual Specificity Phosphoprotein Phosphatase; MAP Kinases (MAPKs); Signal Transduction; mTOR Complex (mTORC).
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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Activating Transcription Factor 1 / genetics
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Activating Transcription Factor 1 / metabolism
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Activating Transcription Factor 2 / genetics
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Activating Transcription Factor 2 / metabolism
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Animals
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Antibiotics, Antineoplastic / pharmacology*
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Benzamides
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Bone Marrow Cells / cytology
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Bone Marrow Cells / enzymology*
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CREB-Binding Protein / genetics
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CREB-Binding Protein / metabolism
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Cell Line
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Dose-Response Relationship, Drug
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Dual Specificity Phosphatase 1 / biosynthesis*
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Dual Specificity Phosphatase 1 / genetics
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Enzyme Activation / drug effects
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Enzyme Activation / genetics
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Enzyme Induction / drug effects
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Enzyme Induction / genetics
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Interleukin-6 / genetics
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Interleukin-6 / metabolism
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Lipopolysaccharides / toxicity
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MAP Kinase Kinase 1 / genetics
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MAP Kinase Kinase 1 / metabolism*
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MAP Kinase Kinase 2 / genetics
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MAP Kinase Kinase 2 / metabolism*
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MAP Kinase Signaling System / drug effects*
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MAP Kinase Signaling System / genetics
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Macrophages / cytology
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Macrophages / enzymology*
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Mice
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Mice, Knockout
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Morpholines / pharmacology
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Nitric Oxide / genetics
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Nitric Oxide / metabolism
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Phosphorylation / drug effects
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Phosphorylation / genetics
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / metabolism*
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Pyrimidines
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Sirolimus / pharmacology*
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TOR Serine-Threonine Kinases / genetics
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TOR Serine-Threonine Kinases / metabolism
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p38 Mitogen-Activated Protein Kinases / genetics
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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Activating Transcription Factor 1
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Activating Transcription Factor 2
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Antibiotics, Antineoplastic
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Atf1 protein, mouse
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Atf2 protein, mouse
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Benzamides
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Interleukin-6
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Lipopolysaccharides
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Morpholines
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Pyrimidines
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vistusertib
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Nitric Oxide
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CREB-Binding Protein
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Crebbp protein, mouse
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mTOR protein, mouse
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Akt1 protein, mouse
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Proto-Oncogene Proteins c-akt
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TOR Serine-Threonine 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, mouse
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Map2k2 protein, mouse
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Dual Specificity Phosphatase 1
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Dusp1 protein, mouse
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Sirolimus