Figure 6.

Schematic presentation of the mechanisms and factors affecting elimination of cells brought to contact with hepatocyte surface. In opposite to the previous opinion, hepatocytes intrinsically transcribe perforin, as well as CD95 and CD95 ligand (CD95L) and can utilize both perforin-granzyme B (GrB) and CD95L-CD95 pathways to kill other cells. The acquired experimental data indicate that hepatocytes can recognize other cells via interaction between desialylated glycoproteins on the target cell surface and asialoglycoprotein receptor (ASGPR) on hepatocyte plasma membrane. (A) Normal hepatocytes show ability to eliminate contacted cells by both CD95L- and perforin-dependent mechanisms. ASGPR involvement in this process is supported by demonstration that desialylation of surface glycoproteins on target cells enhanced their susceptibility to hepatocyte-mediated killing and that inhibition of hepatocyte ASGPR by asilofetuin, a ASGPR-specific ligand, or by silencing of ASGPR gene by specific siRNA significantly limited hepatocyte-facilitated cell killing. (B) The hepatocyte capacity to eliminate cells brought to contact with their surface is augmented after hepatocyte exposure to IFN-γ or TNF-α. This appears to be a consequence of the combined effects of enhanced expression of the cytotoxic effector molecules and augmented display of ASGPR on hepatocyte surface (indicated by arrows with continuous stamps). In chronic WHV hepatitis and resolved acute WHV infection, hepatocyte CD95L- and perforin-dependent cytotoxicity is augmented when compared to hepatocytes from livers of healthy woodchucks. This appears to be a consequence of liver inflammation caused by WHV which progression and resolution are associated with augmented production of many bioactive factors including IFN-γ and TNF-α. It also is possible that the augmented hepatocyte cytotoxicity in some situations could be due to a direct effect of virus (WHx protein) via upregulated expression of the cytotoxic effector molecules or ASGPR in hepatocytes (marked by arrows with dashed stamps). For details see Guy et al. (149–151), Guy et al. (152).