Interleukin-21 mediates hepatitis B virus-associated liver cirrhosis by activating hepatic stellate cells

Aim: Interleukin-21 (IL-21) is involved in effective primary hepatic immune response against hepatitis B virus (HBV) and profibrotic function. However, the role of IL-21 in HBV-associated liver cirrhosis is poorly understood. This study aimed to investigate the role of IL-21 in HBV-associated liver cirrhosis and possible mechanisms. Methods: The study subjects included 10 healthy controls and 30 patients with HBV-associated liver cirrhosis that categorized into three subgroups based on Child-Pugh score (A, 13; B, 10; C, 7). The frequencies of IL-21(+)CD4(+) T cells were detected by flow cytometry, and the level of IL-21 in plasma was measured by enzyme-linked immunoassay. The distribution of IL-21(+) cells in situ in liver was observed by immunohistochemistry. In addition, the in vitro expression of alpha-smooth muscle actin (alpha-SMA), apoptosis and proliferation markers of LX-2 cells were examined by flow cytometry and Cell Counting Kit-8 kit. Finally, the collagen levels in the supernatant were measured by chemiluminescence. Results: Increased peripheral number of IL-21(+)CD4(+) cells, elevated plasma level of IL-21 and IL-21(+) cell accumulation in liver were observed in patients with HBV-associated liver cirrhosis. In vitro administration of IL-21 was accompanied with increased expression of alpha-SMA, inhibited LX-2 cells apoptosis and upregulated collagen production by LX-2 cells. Conclusion: IL-21 may contribute to the fibrogenesis of HBV-associated liver cirrhosis by activating the hepatic stellate cells. Therefore, neutralization of IL-21 could be a favorable new therapeutic strategy for liver cirrhosis treatment.