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.
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.
Oguro
Takiko
T
Department of Biochemical Toxicology, School of Pharmaceutical Sciences, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, 142-8555, Tokyo, Japan.
Takahashi
Yuko
Y
Ashino
Takashi
T
Takaki
Atsushi
A
Shioda
Seiji
S
Horai
Reiko
R
Asano
Masahide
M
Sekikawa
Kenji
K
Iwakura
Yoichiro
Y
Yoshida
Takemi
T
D000818:Animals; D015870:Gene Expression / Q000187:drug effects; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics*; D051547:Heme Oxygenase-1; D007375:Interleukin-1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D048031:JNK Mitogen-Activated Protein Kinases; D008070:Lipopolysaccharides / Q000633:toxicity*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology* / Q000502:physiology; D008565:Membrane Proteins; D008668:Metallothionein / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009569:Nitric Oxide / Q000502:physiology; D010766:Phosphorylation; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases
D007375:Interleukin-1; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D008668:Metallothionein; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases