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

摘要: Mitogen-activated protein kinase phosphatase-1 (MKP-1), also known as dual specificity (DUSP-1), plays a crucial role in the deactivation of MAPKs. Several drugs with immune-suppressive properties modulate MKP-1 expression part their mechanism action. We investigated effect mTOR inhibition through rapamycin and inhibitor (AZD2014) on expression. Low dose led to rapid activation both AKT ERK pathways subsequent increase Rapamycin treatment phosphorylation CREB, transcription factor 1 (ATF1), ATF2, three factors that bind cyclic AMP-responsive elements Mkp-1 promoter. Inhibition either MEK/ERK or pathway attenuated rapamycin-mediated induction. AZD2014 did not activate but activated pathway, leading moderate Using bone marrow-derived macrophages (BMDMs) derived from wild-type (WT) mice deficient AKT1 AKT2 isoforms BMDM targeted deficiency MEK1 MEK2, we show an increased MKP1 WT failed do so BMDMs lacking isoform MEK2. Importantly, pretreatment inhibited LPS-mediated p38 decreased nitric oxide IL-6 production. Our work provides conceptual framework for observed immune modulatory inhibition.