Involvement of tumor necrosis factor alpha, rather than interleukin-1alpha/beta or nitric oxides in the heme oxygenase-1 gene expression by lipopolysaccharide in the mouse liver

FEBS Lett. 2002 Apr 10;516(1-3):63-6. doi: 10.1016/s0014-5793(02)02502-4.


Heme oxygenase-1 (HO-1) is induced under various oxidative stress conditions, such as lipopolysaccharide (LPS) insult. Induction of HO-1 by LPS is reported to be mediated through interleukin-1beta (IL-1beta), rather than other inflammatory cytokines in the mouse liver. However, we found that IL-1alpha/beta knockout (KO) mice responded well to LPS insult, as did wild-type mice with respect to HO-1 mRNA induction (about 30-fold increase). In contrast, tumor necrosis factor alpha KO (TNFalphaKO) mice responded very weakly to LPS in the HO-1 mRNA expression, but not metallothionein mRNA. Recent studies reveal that nitric oxide from Kupffer cells is involved in HO-1 induction in the liver produced by LPS. Therefore, nitrite and nitrate concentrations in the liver were also measured and these parameters did not increase in either IL-1KO or TNFalphaKO. In addition, the phosphorylation of c-JUN N-terminal kinase (JNK) and p38, but not extracellular signal-regulated kinase, was very low in TNFalphaKO mice due to LPS administration. All of these findings indicate that TNFalpha is a major candidate to trigger HO-1 induction in response to LPS stimulation, and that its message is likely transduced through JNK and p38 pathways.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Gene Expression / drug effects
  • Heme Oxygenase (Decyclizing) / genetics*
  • Heme Oxygenase-1
  • Interleukin-1 / deficiency
  • Interleukin-1 / genetics
  • Interleukin-1 / physiology
  • JNK Mitogen-Activated Protein Kinases
  • Lipopolysaccharides / toxicity*
  • Liver / drug effects*
  • Liver / enzymology*
  • Liver / physiology
  • Membrane Proteins
  • Metallothionein / genetics
  • Mice
  • Mice, Knockout
  • Mitogen-Activated Protein Kinases / metabolism
  • Nitric Oxide / physiology
  • Phosphorylation
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / genetics
  • Signal Transduction
  • Tumor Necrosis Factor-alpha / deficiency
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / physiology*
  • p38 Mitogen-Activated Protein Kinases


  • Interleukin-1
  • Lipopolysaccharides
  • Membrane Proteins
  • RNA, Messenger
  • Tumor Necrosis Factor-alpha
  • Nitric Oxide
  • Metallothionein
  • Heme Oxygenase (Decyclizing)
  • Heme Oxygenase-1
  • Hmox1 protein, mouse
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases