The role of Kupffer cell activation in immune liver damage induced by trichloroethylene associated with the IFN-γ/STAT1 signaling pathway.

Trichloroethylene (TCE) is a metal detergent commonly used in industry that can enter the human body through the respiratory tract and skin, causing occupational medicamentosa-like dermatitis due to TCE (OMDT) and multiple organ damage, including liver failure. However, the pathogenesis of liver injury remains unclear. Kupffer cells (KCs) are important tissue macrophages in the body because the polarization of KCs plays a crucial role in immune-mediated liver injury. However, the mechanism of KCs polarization in TCE-induced immune liver injury has not been thoroughly elucidated. In this study, we investigated the effect of TCE-induced KCs polarization on liver function and signal transduction pathways using the TCE sensitization model developed by our group. BALB/c mouse skin was exposed to TCE for sensitization, and an increase in the expression of M1 macrophage-specific markers (CD16/CD32, iNOS), M1 macrophage-specific cytokines IL-1ß, and IFN-γ, P-JAK-1 and P-STAT1 levels were also found to be dramatically increased. When using low doses of gadolinium trichloride (GdCl3), the expression of these proteins and mRNA was significantly reduced. This phenomenon indicates that GdCl3 blocks TCE-induced polarization of KCs and suggests that the IFN-γ/STAT1 signaling pathway may be involved in the polarization process of KCs. These findings clarify the relationship between the polarization of KCs and immune liver injury and highlight the importance of further study of immune-mediated liver injury in TCE-sensitized mice.

Kupffer cell depletion attenuates IL-6/STAT3 mediates hepatocyte apoptosis in immunological liver injury of trichloroethylene sensitized mice.

Trichloroethylene (TCE) induced TCE hypersensitivity syndrome which makes immune injuries in multi-system. The multiple organ damage included skin, liver, kidney and so on. The main manifestations of liver injuries were apoptosis and edema of hepatocytes. In our previous research, we found the activation of Kupffer cells (KCs) which increased IL-6 can aggravate liver cell apoptosis in TCE sensitized mice. However, the mechanism of IL-6 in liver damages induced by TCE was not clear. This study explored the function of IL-6/STAT3 signal pathway on the TCE induced apoptosis of liver cell. We established a TCE sensitized BALB/c mouse model with a KCs inhibitor GdCl3, we found that the expressions of ALT and AST in TCE sensitization positive mice were higher than other mice, and the expressions of apoptosis-related proteins were up-regulated in TCE sensitization positive mice, GdCl3 could alleviate this process. Meanwhile, GdCl3 could significantly decrease the expressions of IL-6/STAT3 proteins. All in all, the activation of KCs can increase the expression of IL-6, IL-6R and phosphorylate STAT3, induces hepatocyte apoptosis, and participates in immunity damage of liver which induced by TCE.

Kupffer cell inactivation ameliorates immune liver injury via TNF-α/TNFR1 signal pathway in trichloroethylene sensitized mice.

METHODS: 36 female BALB/c mice were selected and randomly divided the mice into four groups. We established a BALB/c mouse model of TCE sensitization and pretreatment with GdCl3 (40 mg/kg) by intraperitoneal injection during the during the 17th and 19th days. RESULTS: We found F4/80, the marker of Kupffer cell, was increased in TCE positive group. GdCl3 treatment successfully blocked the activation of Kupffer cell. TNF-α was increased significantly in liver of TCE sensitized mice and decreased significantly when low-dose GdCl3 was used. We found TNF receptor 1 (TNFR1) was increased significantly and GdCl3 treatment resumed the expression of TNFR1 to normal level, as well as the F4/80, TNF-α and TNFR1 mRNA. We also found both caspase-8 and caspase-3 increased in TCE positive group and decreased in TCE + GdCl3 positive group. The number of apoptotic cells in TCE sensitized mice increased by TUNEL staining, and GdCl3 treatment alleviated this increase. Some cells showed edema and inflammatory cell aggregation in liver of TCE positive group, while in the TCE + GdCl3 positive group, the cytoplasm became loose and vacuole-like degeneration occurred. CONCLUSION: Our study unveils cross-talk between Kupffer cell activation and TNFR1 which mediate apoptosis in liver of TCE sensitized mice.