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The Role of the NADPH Oxidase Complex, p38 MAPK, and Akt in Regulating Human Monocyte/Macrophage Survival

Dorothy M. Davis Heart and Lung Research Institute, Department of Internal Medicine, and Department of Surgery, Ohio State University, Columbus, Ohio

Correspondence and requests for reprints should be addressed to Clay B. Marsh, Room 201, Dorothy M. Davis Heart and Lung Research Institute, Ohio State University Medical Center, Columbus, OH 43210. E-mail: Clay.Marsh{at}osumc.edu

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.

Key Words: Akt • macrophage/monocyte • p47^phox • p38 MAP • ROS

CLINICAL RELEVANCE This study provides insight into mechanisms underlying ROS-regulated cellular survival in normal monocytes and macrophages. It also provides supportive evidence for ROS-related cancer and inflammatory diseases therapy.

 

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