14 Toxin-mediated liver injury occurs largely through the generation of ROS and direct mitochondrial damage, leading to hepatic necrosis with

a lesser degree of apoptosis.33 By inducing both the antioxidant superoxide dismutase (SOD) and antiapoptotic regulators (e.g., A20 and Bcl-xl), LPS-induced NF-κB activation is cytoprotective in a broad spectrum of liver injuries mediated by death-receptor ligands and liver toxins. It is of note that the injection of exogenous LPS transiently exaggerated DEN-induced liver damage. This enhanced damage is most likely due to the synergistic effects of DEN-induced hepatic insult and cytokine-induced toxicity following the activation of Kupffer cells by LPS.34 However, the GSK1120212 order rapid decrease in serum alanine aminotransferase (ALT) level in these treated mice suggests that the activation of TLR4 signaling in hepatocytes tilts the balance toward liver protection upon DEN exposure. Previous studies have shown that there is a positive correlation

between cell death and tumor load.14,31,35 It has been suggested that the response of stromal cells such as Kupffer cells to the death of hepatocytes is crucial to the proliferation and expansion of pre-cancerous Ixazomib cells and tumor promotion.14 However, in the TLR4−/− mice aggravated liver click here injury did not lead to an increased tumor load. Our data showed that DEN-induced liver injury was accompanied by elevation of plasma LPS level. LPS can promote the cytokine production and hepatocytes

compensatory proliferation by activating TLR4 expressed on myeloid cells, also it may have a protective role on the initiated cells by activating TLR4 on hepatocytes. TLR4 deficiency ablated the effects of the LPS, so the TLR4−/− mice displayed more severe liver damage, lower cytokine production and hepatocytes proliferation. Accordingly, the chimeric mice with wild type bone marrow had higher levels of cytokines (TNFα and IL-6) and more proliferating hepatocytes than mice with TLR4−/− bone marrow. In addition to LPS, TLR4 has many endogenous ligands, such as high mobility group box (HMGB) 1, Heat Shock Proteins (HSPs), most of which were released by necrotic cells36 In conclusion, our data showed that LPS/TLR4 played an important role in the DEN-induced hepatocarcinogenesis. Recognition of commensal bacteria by TLR4 is crucial in the control of intestinal epithelial homeostasis and protection from direct injury, the disturbance of which can result in severe chronic inflammatory bowel disease (IBD)23 Here, we show that TLR4 activation also affected tissue homeostasis in the adult liver following injury.