title: Rapamycin induces mitogen-activated protein (MAP) kinase phosphatase-1 (MKP-1) expression through activation of protein kinase B and mitogen-activated protein kinase kinase pathways.
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.
authors.affiliation: Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, Wayne State University School of Medicine and Detroit Medical Center, Detroit, Michigan 48201.
authors.forename: Ruchi
authors.initials: R
authors.lastname: Rastogi
authors.affiliation: Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, Wayne State University School of Medicine and Detroit Medical Center, Detroit, Michigan 48201.
authors.forename: Zhongliang
authors.initials: Z
authors.lastname: Jiang
authors.affiliation: Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, Wayne State University School of Medicine and Detroit Medical Center, Detroit, Michigan 48201.
authors.forename: Nisar
authors.initials: N
authors.lastname: Ahmad
authors.affiliation: Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, Wayne State University School of Medicine and Detroit Medical Center, Detroit, Michigan 48201.
authors.forename: Rita
authors.initials: R
authors.lastname: Rosati
authors.affiliation: The Research Institute at Nationwide Children's Hospital, Columbus, Ohio 43205.
authors.forename: Yusen
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Centre de Recherche sur le Cancer de l'Université Laval, CRCHU-Q, L'Hôtel-Dieu de Québec, Québec G1R 2J6, Canada.
authors.forename: Laurent
authors.initials: L
authors.lastname: Beuret
authors.affiliation: Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104.
authors.forename: Robert
authors.initials: R
authors.lastname: Monks
authors.affiliation: Centre de Recherche sur le Cancer de l'Université Laval, CRCHU-Q, L'Hôtel-Dieu de Québec, Québec G1R 2J6, Canada.
authors.forename: Jean
authors.initials: J
authors.lastname: Charron
authors.affiliation: Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104.
authors.forename: Morris J
authors.initials: MJ
authors.lastname: Birnbaum
authors.affiliation: Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, Wayne State University School of Medicine and Detroit Medical Center, Detroit, Michigan 48201; Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, Michigan 48201. Electronic address: lsamavat@med.wayne.edu.
authors.forename: Lobelia
authors.initials: L
authors.lastname: Samavati
mesh_terms: D051697:Activating Transcription Factor 1 / Q000235:genetics / Q000378:metabolism; D051698:Activating Transcription Factor 2 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D001549:Benzamides; D001854:Bone Marrow Cells / Q000166:cytology / Q000201:enzymology*; D050882:CREB-Binding Protein / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D054638:Dual Specificity Phosphatase 1 / Q000096:biosynthesis* / Q000235:genetics; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D004790:Enzyme Induction / Q000187:drug effects / Q000235:genetics; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D048369:MAP Kinase Kinase 1 / Q000235:genetics / Q000378:metabolism*; D048370:MAP Kinase Kinase 2 / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000235:genetics; D008264:Macrophages / Q000166:cytology / Q000201:enzymology*; D051379:Mice; D018345:Mice, Knockout; D009025:Morpholines / Q000494:pharmacology; D009569:Nitric Oxide / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D011743:Pyrimidines; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D051697:Activating Transcription Factor 1; D051698:Activating Transcription Factor 2; D000903:Antibiotics, Antineoplastic; C497100:Atf1 protein, mouse; C497106:Atf2 protein, mouse; D001549:Benzamides; D015850:Interleukin-6; D008070:Lipopolysaccharides; D009025:Morpholines; D011743:Pyrimidines; C585537:vistusertib; D009569:Nitric Oxide; D050882:CREB-Binding Protein; C494364:Crebbp protein, mouse; C546843:mTOR protein, mouse; C514862:Akt1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482127:Map2k1 protein, mouse; C482129:Map2k2 protein, mouse; D054638:Dual Specificity Phosphatase 1; C517020:Dusp1 protein, mouse; D020123:Sirolimus
keywords: Akt PKB; Dual Specificity Phosphoprotein Phosphatase; MAP Kinases (MAPKs); Signal Transduction; mTOR Complex (mTORC)