Phosphatidylinositol 3-kinase/Akt pathway mediates heme oxygenase-1 regulation by lipopolysaccharide. Academic Article uri icon

Overview

MeSH

  • Animals
  • Cell Line
  • Gene Expression Regulation
  • Inflammation
  • Macrophages
  • Mice
  • NF-E2-Related Factor 2
  • Promoter Regions, Genetic
  • Transfection
  • p38 Mitogen-Activated Protein Kinases

MeSH Major

  • Heme Oxygenase-1
  • Lipopolysaccharides
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt

abstract

  • The stress-inducible protein heme oxygenase-1 exerts potent antiinflammatory, antiapoptotic and cytoprotective effects in vitro and in vivo. Another important mediator of cytoprotection, the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway activates many proteins involved in the maintenance of cellular homeostasis. Since activation of heme oxygenase-1 and PI3K/Akt both protect the cellular environment, we postulated that PI3K/Akt can regulate the induction of heme oxygenase-1 by proinflammatory stress. The treatment of primary murine macrophage cells (RAW 264.7) with lipopolysaccharide induced heme oxygenase-1 protein and mRNA expression, and increased the phosphorylation of Akt and p38 mitogen activated protein kinase (p38 MAPK). These cellular effects of lipopolysaccharide were markedly diminished by pre-treatment with wortmannin, a specific inhibitor of PI3K. Furthermore, lipopolysaccharide-inducible heme oxygenase expression was blocked by SB203580, a specific inhibitor of p38 MAPK. Both wortmannin and SB203580 decreased lipopolysaccharide-inducible NF-E2-related factor (Nrf2) DNA binding activity. Transfection of macrophages with dominant negative mutants of PI3K, Akt and Nrf2, as well as wortmannin treatment, significantly reduced the transcriptional activity of a minimal heme oxygenase-1 promoter luciferase construct (D33HO-1luc). We demonstrate, to our knowledge for the first time, that upon proinflammatory stimulation heme oxygenase-1 gene expression in macrophages depends on PI3K/Akt and p38 MAPK acting upstream of Nrf2-dependent promoter activation.

publication date

  • October 3, 2005

has subject area

  • Animals
  • Cell Line
  • Gene Expression Regulation
  • Heme Oxygenase-1
  • Inflammation
  • Lipopolysaccharides
  • Macrophages
  • Mice
  • NF-E2-Related Factor 2
  • Phosphatidylinositol 3-Kinases
  • Promoter Regions, Genetic
  • Proto-Oncogene Proteins c-akt
  • Transfection
  • p38 Mitogen-Activated Protein Kinases

Research

keywords

  • Journal Article

Identity

Language

  • eng

PubMed ID

  • 16309568

Additional Document Info

start page

  • 461

end page

  • 470

volume

  • 51

number

  • 5