The Effects of CD100 Stimulation on Primary Human Hepatocytes (PHHs) and Its Implications in HBV-Related Liver Cirrhosis.

BACKGROUND

CD100 is a positive regulator for immune responses. In HBV infection, CD100 can regulate immune cell activation for antiviral responses, raising the possibility that it might become a potential target for the treatment of HBV-related liver cirrhosis. However, the CD100 impact on hepatocytes and its influence in HBV-related liver cirrhosis have yet to be determined.

METHODS

The sCD100 in the serum and the CD100 on platelets were analyzed in HBV-infected patients. The effects of CD100 stimulation on primary human hepatocytes (PHHs) and the gene expressions in human liver tissues during HBV-related liver cirrhosis were examined by mRNA-microarray analysis. GO and PPI enrichments were used to evaluate shared genes of CD100-regulated genes in PHHs and changed genes in liver tissues. The influence of CD100 on the activation of hepatic stellate cells (HSCs) and extracellular matrix deposition was assessed in a PHHs and HSCs co-culture system.

RESULTS

The serum sCD100 and CD100 on platelets, which possess the potential to directly interact with hepatocytes, were downregulated in HBV-infected patients. The CD100 stimulation induced immune responses, elevated the expression of TGF-β antagonists and HNF4A-related genes, and inhibited ECM deposition in the PHHs and HSCs co-culture system. CD100 modulated the gene expression in PHHs through plexin B1 and B2 signal transduction, which activated the ERK and STAT3 signaling pathway.

CONCLUSION

CD100 stimulation on PHHs induced anti-cirrhosis gene expression and suppressed HSCs activation through ERK and STAT3 signaling, which may potentially serve as a target for the treatment of HBV-related liver cirrhosis.