title: The role of the NADPH oxidase complex, p38 MAPK, and Akt in regulating human monocyte/macrophage survival.
abstract: M-CSF induces PI 3-kinase activation, resulting in reactive oxygen species (ROS) production. Previously, we reported that ROS mediate macrophage colony-stimulating factor (M-CSF)-induced extracellular regulated kinase (Erk) activation and monocyte survival. In this work, we hypothesized that M-CSF-stimulated ROS products modulated Akt1 and p38 activation. Furthermore, we sought to clarify the source of these ROS and the role of ROS and Akt in monocyte/macrophage survival. Macrophages from p47(phox-/-) mice, lacking a key component of the NADPH oxidase complex required for ROS generation, had reduced cell survival and Akt1 and p38 mitogen-activated protein kinase (MAPK) phosphorylation compared with wild-type macrophages in response to M-CSF stimulation, but had no difference in M-CSF-stimulated Erk. To understand how ROS affected monocyte survival and signaling, we observed that NAC and DPI decreased cell survival and Akt1 and p38 MAPK phosphorylation. Using bone marrow-derived macrophages from mice expressing constitutively activated Akt1 (Myr-Akt1) or transfecting Myr-Akt1 constructs into human peripheral monocytes, we concluded that Akt is a positive regulator of monocyte survival. Moreover, the p38 MAPK inhibitor, SB203580, inhibited p38 activity and M-CSF-induced monocyte survival. These findings demonstrate that ROS generated from the NADPH oxidase complex contribute to monocyte/macrophage survival induced by M-CSF via regulation of Akt and p38 MAPK.
authors.affiliation: Dorothy M Davis Heart and Lung Research Institute, Department of Internal Medicine, Ohio State University Medical Center, Columbus, OH 43210, USA.
authors.forename: Yijie
authors.initials: Y
authors.lastname: Wang
authors.forename: Mandy M
authors.initials: MM
authors.lastname: Zeigler
authors.forename: Gregory K
authors.initials: GK
authors.lastname: Lam
authors.forename: Melissa G
authors.initials: MG
authors.lastname: Hunter
authors.forename: Tim D
authors.initials: TD
authors.lastname: Eubank
authors.forename: Valery V
authors.initials: VV
authors.lastname: Khramtsov
authors.forename: Susheela
authors.initials: S
authors.lastname: Tridandapani
authors.forename: Chandan K
authors.initials: CK
authors.lastname: Sen
authors.forename: Clay B
authors.initials: CB
authors.lastname: Marsh
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000502:physiology; D002470:Cell Survival; D002478:Cells, Cultured; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D016173:Macrophage Colony-Stimulating Factor / Q000502:physiology; D008264:Macrophages / Q000502:physiology; D051379:Mice; D009000:Monocytes / Q000502:physiology*; D019255:NADPH Oxidases / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D007093:Imidazoles; D011725:Pyridines; D017382:Reactive Oxygen Species; D016173:Macrophage Colony-Stimulating Factor; D019255:NADPH Oxidases; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580