TLR4 mediates LPS-induced HO-1 expression in mouse liver: role of TNF-alpha and IL-1beta

World J Gastroenterol. 2003 Aug;9(8):1799-803. doi: 10.3748/wjg.v9.i8.1799.


Aim: Heme oxygenase (HO)-1 catalyzes the conversion of heme to biliverdin, iron and carbon monoxide. HO-1 is induced by many stimuli including heme, Hb, heat stress,lipopolysaccharide (LPS) and cytokines. Previous studies demonstrated that LPS induced HO-1 gene activation and HO-1 expression in liver. However, the mechanisms of LPS-induced HO-1 expression in liver remain unknown. The effect of toll-like receptor-4 (TLR4) on LPS-induced liver HO-1 expression and the role of TNF-alpha and IL-1beta in this condition were determined.

Methods: HO-1 expression was determined by immunofluorescent staining and immunoblotting. Double immunofluorescent staining was performed to determine the cell type of HO-1 expression in liver.

Results: A low dose of LPS significantly increased HO-1 expression in the liver which was localized in Kupffer cells only. Furthermore, HO-1 expression was enhanced by three doses of LPS. HO-1 expression was significantly inhibited in the liver of TLR4 mutant mice. While the liver HO-1 expression in TNF KO mice was much lower than that in C57 mice following the same LPS treatment, IL-1beta KO had a slight influence on liver HO-1 expression following LPS treatment.

Conclusion: The present results confirm that macrophages are the major source of HO-1 in the liver induced by LPS. This study demonstrates that TLR4 plays a dominant role in mediating HO-1 expression following LPS. LPS-induced HO-1 expression is mainly mediated by endogenous TNF-alpha, but only partially by endogenous IL-1beta.

MeSH terms

  • Animals
  • Heme Oxygenase (Decyclizing) / metabolism*
  • Heme Oxygenase-1
  • In Vitro Techniques
  • Interleukin-1 / physiology
  • Lipopolysaccharides / pharmacology*
  • Liver / metabolism*
  • Male
  • Membrane Glycoproteins / physiology*
  • Membrane Proteins
  • Mice
  • Mice, Inbred Strains
  • Receptors, Cell Surface / physiology*
  • Toll-Like Receptor 4
  • Toll-Like Receptors
  • Tumor Necrosis Factor-alpha / physiology


  • Interleukin-1
  • Lipopolysaccharides
  • Membrane Glycoproteins
  • Membrane Proteins
  • Receptors, Cell Surface
  • Toll-Like Receptor 4
  • Toll-Like Receptors
  • Tumor Necrosis Factor-alpha
  • Heme Oxygenase (Decyclizing)
  • Heme Oxygenase-1
  • Hmox1 protein, mouse