15, 16 Additionally, the expression of NK cell inhibitory ligand MHC I is down-regulated,17 whereas TRAIL receptor expression is up-regulated in activated HSCs,18, 19 which may represent additional important mechanisms contributing to increased sensitivity

of HCSs to NK cell/TRAIL killing. At present, it is not clear whether expression of NKG2D ligands (MICA/B) is also up-regulated in activated human HSCs during chronic liver diseases. Although Kahraman et al.13 performed immunohistochemical analyses of NASH liver samples with MICA/B antibodies, the expression of MICA/B on the HSCs Olaparib price was not well illustrated. Double-staining with MICA/B antibodies and HSC markers will be required in the future to identify whether MICA/B proteins are expressed on activated HSCs in patients with chronic liver disease. In addition to having

a beneficial effect on liver fibrosis, the interaction of NKG2D and corresponding ligands may also play an important role in immunosurveillance against cholangiocarcinoma and hepatocellular carcinoma. Genetic analyses of NKG2D polymorphisms strongly suggest that interaction of NKG2D-MICA protects against cholangiocarcinoma in patients with primary sclerosing cholangitis.20 The inhibitory effect of NKG2D on liver tumors is likely mediated via activation of NK cells and the subsequent production of TRAIL, which is a potent cytotoxic mediator that kills hepatocellular carcinoma and cholangiocarcinoma cells.21 However, MICA/B proteins are also cleaved proteolytically from hepatocellular carcinoma cells Volasertib ic50 and appear as soluble particles in serum from these patients.22 These soluble MICA/B proteins can down-regulate NKG2D expression and inhibit NKG2D-mediated NK cytotoxicity against liver tumor cells,23 allowing tumor cells to escape from immunity attacks mediated

by NKG2D. In summary, interaction between NKG2D and ligands can trigger NK cell activation, playing an important role in host defenses against hepatitis viral infection and liver cancer development, as well as the inhibition of liver fibrosis (Fig 1). Such activation may also contribute to hepatocellular damage in patients with HCV infection and NAFL/NASH. Additionally, the down-regulation medchemexpress of this activation (e.g., by alcohol drinking) may accelerate the progression of liver disease, including viral infection and liver fibrosis,24, 25 while up-regulation of NKG2D expression on NK cells by poly I:C and IFN-γ can markedly enhance NK cell cytotoxicity against hepatocytes and HSCs, leading to hepatocellular damage and the reduction of liver fibrosis, respectively.11, 15 Interestingly, treating mice with IFN-α also markedly increased expression of NKG2D on liver NK cells (our unpublished data).