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Importance of direct hepatocytolysis by liver macrophages in experimental fulminant hepatitis
H Tsutsui1, Y Mizoguchi, S Morisawa
1First Department of Biochemistry, Osaka City University Medical School, Japan.
Abstract:
When lipopolysaccharide was administered to mice that had been injected with heat-killed Propionibacterium acnes, most of them died of massive liver necrosis. Previously, we demonstrated that a soluble hepatocytotoxic factor released by liver adherent cells fully activated by both P. acnes and lipopolysaccharide was attributable to the late stage of this severe liver injury. In this report, we focused on the hepatocytolysis by these liver adherent cells in a cell-cell interaction manner. Shortly after stimulation with lipopolysaccharide, the P. acnes-elicited liver adherent cells almost completely killed the hepatocytes prepared from both normal syngeneic mice and P. acnes-treated ones. Since P. acnes-elicited liver adherent cells also proved to produce various kinds of cytokines in a short time, the role of cytokines in this liver injury was analyzed. Only TNF-alpha enabled the P. acnes-elicited liver adherent cells to kill hepatocytes prepared from the same mice, but none from the normal ones. These results suggest that the liver adherent cells accumulated and partly stimulated by P. acnes-treatment might rapidly lyse the autologous hepatocytes once triggered by lipopolysaccharide and that the TNF-alpha these liver adherent cells produced might upregulate their own hepatocytotoxic ability.
Insights
Propionibacterium acnes and lipopolysaccharide trigger liver adherent cells to kill hepatocytes. Tumor necrosis factor-alpha (TNF-α) enhances this cell-mediated liver injury, contributing to severe liver damage.
Area of Science:
- Immunology
- Hepatology
- Cell Biology
Background:
- Heat-killed Propionibacterium acnes (P. acnes) combined with lipopolysaccharide (LPS) induces lethal liver necrosis in mice.
- Previous research identified a soluble hepatocytotoxic factor from activated liver adherent cells as a cause of late-stage liver injury.
Purpose of the Study:
- To investigate the direct cell-cell interaction mechanism of hepatocytolysis mediated by P. acnes-elicited liver adherent cells.
- To determine the role of cytokines, particularly TNF-alpha, in this P. acnes and LPS-induced liver injury.
Main Methods:
- Primary hepatocytes and liver adherent cells were isolated from normal and P. acnes-treated syngeneic mice.
- Cell-cell interaction assays were performed to assess hepatocyte lysis following LPS stimulation.
- Cytokine production by liver adherent cells was analyzed, with a focus on TNF-alpha's role.
Main Results:
- P. acnes-elicited liver adherent cells rapidly killed autologous hepatocytes after LPS stimulation.
- Tumor necrosis factor-alpha (TNF-α) was identified as a key cytokine enabling P. acnes-elicited liver adherent cells to lyse hepatocytes.
- This cytotoxic effect was specific to autologous hepatocytes, not those from normal mice.
Conclusions:
- Liver adherent cells, primed by P. acnes, can directly lyse autologous hepatocytes upon LPS challenge.
- TNF-α produced by these cells plays a crucial role in upregulating their hepatocytotoxic potential.
- This cell-mediated mechanism contributes significantly to acute liver injury induced by P. acnes and LPS.