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


CONCLUSIONS
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.
Song
Yong
Y
Department of Respiratory Diseases, Nanjing Jinling Hospital, School of Medicine, Nanjing University, Nanjing 210002, Jiangsu Province, China. yong_song6310@yahoo.com
Shi
Yi
Y
Ao
Li-Hua
LH
Harken
Alden H
AH
Meng
Xian-Zhong
XZ
D000818:Animals; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism*; D051547:Heme Oxygenase-1; D066298:In Vitro Techniques; D007375:Interleukin-1 / Q000502:physiology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008099:Liver / Q000378:metabolism*; D008297:Male; D008562:Membrane Glycoproteins / Q000502:physiology*; D008565:Membrane Proteins; D051379:Mice; D008815:Mice, Inbred Strains; D011956:Receptors, Cell Surface / Q000502:physiology*; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
D007375:Interleukin-1; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D011956:Receptors, Cell Surface; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse