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.

CD100; HNF4A; TGF‐β antagonists; chronic hepatitis B; liver cirrhosis; primary human hepatocytes.