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Lipopolysaccharide-induced heme oxygenase-1 expression in human monocytic cells is mediated via Nrf2 and protein

Stuart A Rushworth1, Xi-Lin Chen, Nigel Mackman

  • 1Medical Research Council Human Nutrition Research, Elsie Widdowson Laboratory, Cambridge, United Kingdom.

Journal of Immunology (Baltimore, Md. : 1950)
|September 24, 2005
PubMed

Insights

Lipopolysaccharide (LPS) induces heme oxygenase 1 (HO-1) in human monocytes via the transcription factor NF-E2-related factor 2 (Nrf2) and protein kinase C (PKC). This pathway is crucial for regulating immune responses during sepsis.

Area of Science:

  • Immunology
  • Molecular Biology
  • Biochemistry

Background:

  • Monocytes are critical for immune responses during sepsis.
  • Lipopolysaccharide (LPS) triggers both pro-inflammatory and regulatory responses in monocytes.
  • Heme oxygenase 1 (HO-1) is a cytoprotective enzyme induced by LPS in macrophages, involving antioxidant-response elements (AREs) and the transcription factor Nrf2.

Purpose of the Study:

  • To investigate the role of Nrf2 in LPS-induced HO-1 expression in human monocytic cells.
  • To elucidate the involvement of protein kinase C (PKC) in this regulatory pathway.

Main Methods:

  • LPS stimulation of human monocytes and THP-1 cells.
  • Analysis of HO-1 mRNA and protein expression.
  • Assessment of Nrf2 translocation and DNA binding to the HO-1 promoter's ARE.
  • Use of dominant-negative Nrf2 mutants.
  • Inhibition of PKC signaling pathways using Ro-31-8220 and Go6976.

Main Results:

  • LPS induced HO-1 mRNA and protein expression in human monocytes and THP-1 cells.
  • LPS treatment led to Nrf2 translocation to the nucleus and binding to the ARE in the HO-1 promoter.
  • A dominant-negative Nrf2 mutant suppressed LPS-induced HO-1 mRNA but not TNF-alpha mRNA expression.
  • PKC inhibitors (Ro-31-8220 and Go6976) reduced LPS-induced HO-1 mRNA expression and blocked Nrf2 binding to the ARE.

Conclusions:

  • LPS-induced HO-1 expression in human monocytic cells is dependent on Nrf2.
  • Protein kinase C (PKC) signaling is essential for LPS-induced Nrf2 activation and subsequent HO-1 expression.
  • This pathway highlights a novel mechanism regulating inflammatory and oxidative stress responses in monocytes during sepsis.

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