Phosphatidylinositol 3-kinase/Akt pathway mediates heme oxygenase-1 regulation by lipopolysaccharide

S. E. Pischke, Z. Zhou, R. Song, W. Ning, J. Alam, S. W. Ryter, A. M.K. Choi

Research output: Contribution to journalArticle

20 Scopus citations

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 (Δ33HO-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.

Original languageEnglish (US)
Pages (from-to)461-470
Number of pages10
JournalCellular and Molecular Biology
Volume51
Issue number5
DOIs
StatePublished - Oct 3 2005

Keywords

  • Akt
  • Hemeoxygenase-1
  • Lipopolysaccharide
  • Mitogen activated protein kinase
  • Nrf2
  • Phosphatidylinositol 3-kinase
  • Stress response
  • p38

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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