Our study was undertaken to evaluate the important role of interleukin-6 (IL-6) trans-signaling in acetaminophen (AAP)-induced liver injury. A soluble gp130 protein (sgp130Fc) exclusively inhibits IL-6 trans-signaling, whereas an IL-6/soluble IL-6 receptor (sIL-6R) fusion protein (hyper-IL-6) mimics IL-6 trans-signaling. Using these tools, we investigated the role of IL-6 trans-signaling in AAP-induced liver injury. Blockade of IL-6 trans-signaling during AAP-induced liver injury remarkably increased the levels of serum aspartate aminotransferase and alanine aminotransferase; lowered the level of serum sIL-6R; aggravated liver injury; inhibited the expression of phosphorylation of STAT3 (pSTAT3), proliferating cell nuclear antigen, vascular endothelial growth factor, and glycogen synthesis; and induced the expression of Caspase3, cytochrome P450 2E1 (CYP2E1), and hepatocyte apoptosis in the liver of mice. In summary, our study suggested that IL-6 trans-signaling plays important protective roles by regulating the hepatocyte proliferation and apoptosis, angiogenesis, CYP2E1 expression, and glycogen metabolism during AAP-induced liver injury in mice.

Our study was undertaken to evaluate the important role that a disintegrin and metalloproteinase 9 (ADAM9) regulates IL-6 trans-signaling in carbon tetrachloride (CCl4)-induced liver injury in mice. Mice were divided into four groups. Each group respectively received mineral oil injection, CCl4 injection, anti-ADAM9 monoclonal antibody (mAb) pretreatment and CCl4 injection, anti-ADAM9 mAb and recombinant mouse ADAM9 molecules pretreatment with CCl4 injection. Our results showed that anti-ADAM9 mAb pretreatment significantly aggravated liver injury, inhibited IL-6 trans-signaling, which led to downregulation of proliferating cell nuclear antigen (PCNA), vascular endothelial growth factor (VEGF), upregulation of Caspase3, cytochrome P450 2E1 (CYP2E1), and hepatocytes apoptosis at 24 h after CCl4 injection. Recombinant ADAM9 molecules pretreatment reversed the impact of anti-ADAM9 mAb pretreatment in mice. In conclusion, our study suggested that ADAM9 could regulate the hepatocytes proliferation, apoptosis, angiogenesis, and CYP2E1 expression by activating IL-6 trans-signaling and play important protective roles during CCl4-induced liver injury in mice.

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ADAM8 (disintegrin and metalloprotease 8) belongs to a family of transmembrane proteins implicated in cell-cell interactions, proteolysis of membrane proteins, and various aspects of carcinogenesis. In tthis study, we want to evaluate whether ADAM8 is highly expressed in liver cancer. So western blot, RT-PCR and Immunohistochemistry were used to evaluate the expression of ADAM8 in liver cancer and normal liver. The results of western blot and RT-PCR show that ADAM8 is highly expressed in liver cancer. The result s of immunohistochemistry shows that ADAM8 is mainly expressed in the cytoplasm of liver cancer cells. Our resuts first prove that ADAM8 is expressed in the liver cancer, which may play important roles in the genesis and development of liver cancer.