PMID- 24126911 OWN - NLM STAT- MEDLINE DCOM- 20140204 LR - 20211203 IS - 1083-351X (Electronic) IS - 0021-9258 (Print) IS - 0021-9258 (Linking) VI - 288 IP - 47 DP - 2013 Nov 22 TI - 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. PG - 33966-33977 LID - S0021-9258(19)54376-9 [pii] LID - 10.1074/jbc.M113.492702 [doi] AB - 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. FAU - Rastogi, Ruchi AU - Rastogi R AD - Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, Wayne State University School of Medicine and Detroit Medical Center, Detroit, Michigan 48201. FAU - Jiang, Zhongliang AU - Jiang Z AD - Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, Wayne State University School of Medicine and Detroit Medical Center, Detroit, Michigan 48201. FAU - Ahmad, Nisar AU - Ahmad N AD - Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, Wayne State University School of Medicine and Detroit Medical Center, Detroit, Michigan 48201. FAU - Rosati, Rita AU - Rosati R AD - Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, Wayne State University School of Medicine and Detroit Medical Center, Detroit, Michigan 48201. FAU - Liu, Yusen AU - Liu Y AD - The Research Institute at Nationwide Children's Hospital, Columbus, Ohio 43205. FAU - Beuret, Laurent AU - Beuret L AD - Centre de Recherche sur le Cancer de l'Universite Laval, CRCHU-Q, L'Hotel-Dieu de Quebec, Quebec G1R 2J6, Canada. FAU - Monks, Robert AU - Monks R AD - Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104. FAU - Charron, Jean AU - Charron J AD - Centre de Recherche sur le Cancer de l'Universite Laval, CRCHU-Q, L'Hotel-Dieu de Quebec, Quebec G1R 2J6, Canada. FAU - Birnbaum, Morris J AU - Birnbaum MJ AD - Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104. FAU - Samavati, Lobelia AU - Samavati L AD - 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. LA - eng GR - R01 DK056886/DK/NIDDK NIH HHS/United States GR - R01 HL113508/HL/NHLBI NIH HHS/United States GR - R01 DK56886/DK/NIDDK NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20131014 PL - United States TA - J Biol Chem JT - The Journal of biological chemistry JID - 2985121R RN - 0 (Activating Transcription Factor 1) RN - 0 (Activating Transcription Factor 2) RN - 0 (Antibiotics, Antineoplastic) RN - 0 (Atf1 protein, mouse) RN - 0 (Atf2 protein, mouse) RN - 0 (Benzamides) RN - 0 (Interleukin-6) RN - 0 (Lipopolysaccharides) RN - 0 (Morpholines) RN - 0 (Pyrimidines) RN - 0BSC3P4H5X (vistusertib) RN - 31C4KY9ESH (Nitric Oxide) RN - EC 2.3.1.48 (CREB-Binding Protein) RN - EC 2.3.1.48 (Crebbp protein, mouse) RN - EC 2.7.1.1 (mTOR protein, mouse) RN - EC 2.7.11.1 (Akt1 protein, mouse) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases) RN - EC 2.7.12.2 (MAP Kinase Kinase 1) RN - EC 2.7.12.2 (MAP Kinase Kinase 2) RN - EC 2.7.12.2 (Map2k1 protein, mouse) RN - EC 2.7.12.2 (Map2k2 protein, mouse) RN - EC 3.1.3.48 (Dual Specificity Phosphatase 1) RN - EC 3.1.3.48 (Dusp1 protein, mouse) RN - W36ZG6FT64 (Sirolimus) SB - IM MH - Activating Transcription Factor 1/genetics/metabolism MH - Activating Transcription Factor 2/genetics/metabolism MH - Animals MH - Antibiotics, Antineoplastic/*pharmacology MH - Benzamides MH - Bone Marrow Cells/cytology/*enzymology MH - CREB-Binding Protein/genetics/metabolism MH - Cell Line MH - Dose-Response Relationship, Drug MH - Dual Specificity Phosphatase 1/*biosynthesis/genetics MH - Enzyme Activation/drug effects/genetics MH - Enzyme Induction/drug effects/genetics MH - Interleukin-6/genetics/metabolism MH - Lipopolysaccharides/toxicity MH - MAP Kinase Kinase 1/genetics/*metabolism MH - MAP Kinase Kinase 2/genetics/*metabolism MH - MAP Kinase Signaling System/*drug effects/genetics MH - Macrophages/cytology/*enzymology MH - Mice MH - Mice, Knockout MH - Morpholines/pharmacology MH - Nitric Oxide/genetics/metabolism MH - Phosphorylation/drug effects/genetics MH - Proto-Oncogene Proteins c-akt/genetics/*metabolism MH - Pyrimidines MH - Sirolimus/*pharmacology MH - TOR Serine-Threonine Kinases/genetics/metabolism MH - p38 Mitogen-Activated Protein Kinases/genetics/metabolism PMC - PMC3837136 OTO - NOTNLM OT - Akt PKB OT - Dual Specificity Phosphoprotein Phosphatase OT - MAP Kinases (MAPKs) OT - Signal Transduction OT - mTOR Complex (mTORC) EDAT- 2013/10/16 06:00 MHDA- 2014/02/05 06:00 PMCR- 2014/11/22 CRDT- 2013/10/16 06:00 PHST- 2013/10/16 06:00 [entrez] PHST- 2013/10/16 06:00 [pubmed] PHST- 2014/02/05 06:00 [medline] PHST- 2014/11/22 00:00 [pmc-release] AID - S0021-9258(19)54376-9 [pii] AID - M113.492702 [pii] AID - 10.1074/jbc.M113.492702 [doi] PST - ppublish SO - J Biol Chem. 2013 Nov 22;288(47):33966-33977. doi: 10.1074/jbc.M113.492702. Epub 2013 Oct 14.