Insulin-induced NADPH oxidase activation promotes proliferation and matrix metalloproteinase activation in monocytes/macrophages

Free Radic Biol Med. 2009 Apr 15;46(8):1058-67. doi: 10.1016/j.freeradbiomed.2009.01.009. Epub 2009 Jan 21.


Insulin stimulates superoxide (O(2)(-)) production in monocytes and macrophages. However, the mechanisms through which insulin induces O(2)(-) production are not completely understood. In this study, we (a) characterized the enzyme and the pathways involved in insulin-stimulated O(2)(-) production in human monocytes and murine macrophages, and (b) analyzed the consequences of insulin-stimulated O(2)(-) production on the cellular phenotype in these cells. We showed that insulin stimulated O(2)(-) production, and promoted p47(phox) translocation to the plasma membrane. Insulin-induced O(2)(-) production and p47(phox) 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 NFkappaB, p38MAPK, and ERK 1/2 activation. Small-interfering RNA-specific gene silencing targeted specifically against Nox2 reduced the cognate protein expression, decreased insulin-induced O(2)(-) production, inhibited the turn on of NFkappaB, 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Cell Proliferation
  • Cells, Cultured
  • Enzyme Activation
  • Enzyme Inhibitors / pharmacology
  • Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
  • Humans
  • Insulin / metabolism*
  • Macrophages / drug effects
  • Macrophages / enzymology*
  • Macrophages / pathology
  • Matrix Metalloproteinase 9 / genetics
  • Matrix Metalloproteinase 9 / metabolism*
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism*
  • Mice
  • Monocytes / drug effects
  • Monocytes / enzymology*
  • Monocytes / pathology
  • NADPH Oxidase 2
  • NADPH Oxidases / genetics
  • NADPH Oxidases / metabolism*
  • NF-kappa B / metabolism
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Kinase C / antagonists & inhibitors
  • Protein Transport / drug effects
  • RNA, Small Interfering / genetics
  • Signal Transduction / drug effects
  • Superoxides / chemistry
  • Superoxides / metabolism
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors


  • Enzyme Inhibitors
  • Insulin
  • Membrane Glycoproteins
  • NF-kappa B
  • Phosphoinositide-3 Kinase Inhibitors
  • RNA, Small Interfering
  • Superoxides
  • Cybb protein, mouse
  • NADPH Oxidase 2
  • NADPH Oxidases
  • neutrophil cytosolic factor 1
  • Protein Kinase C
  • Extracellular Signal-Regulated MAP Kinases
  • p38 Mitogen-Activated Protein Kinases
  • Matrix Metalloproteinase 9