Insulin-induced NADPH oxidase activation promotes proliferation and matrix metalloproteinase activation in monocytes/macrophages |
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Authors: | Gorka San José Julen Bidegain Pablo A. Robador Javier Díez Ana Fortuño Guillermo Zalba |
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Affiliation: | 1. Faculty of Clinical Medicine, Shandong University School of Medicine, Jinan 250012, China;2. Department of Histology and Embryology, Binzhou Medical College, Binzhou, 256603, China;3. Department of Orthopaedics, Shandong University Qilu hospital, Jinan 250012, China;4. Department of Anatomy, Shandong University School of Medicine, Jinan 250012, China |
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Abstract: | Insulin stimulates superoxide (O2?) production in monocytes and macrophages. However, the mechanisms through which insulin induces O2? production are not completely understood. In this study, we (a) characterized the enzyme and the pathways involved in insulin-stimulated O2? production in human monocytes and murine macrophages, and (b) analyzed the consequences of insulin-stimulated O2? production on the cellular phenotype in these cells. We showed that insulin stimulated O2? production, and promoted p47phox translocation to the plasma membrane. Insulin-induced O2? production and p47phox translocation were prevented in the presence of specific inhibitors of PI3K and PKC. Insulin-mediated NADPH oxidase activation stimulated MMP-9 activation in monocytes and cell proliferation in macrophages. The effect of insulin on these phenotypic responses was mediated through NFκB, p38MAPK, and ERK 1/2 activation. Small-interfering RNA-specific gene silencing targeted specifically against Nox2 reduced the cognate protein expression, decreased insulin-induced O2? production, inhibited the turn on of NFκB, p38MAPK, and ERK 1/2, and reduced cell proliferation in macrophages. These findings suggest a pivotal role for NADPH oxidase in insulin-induced proliferation and proteolytic activation in monocytes and macrophages, respectively, and identify a pathway that may play a pathological role in hyperinsulinemic states. |
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