Interleukin-21 is upregulated in hepatitis B-related acute-on-chronic liver failure and associated with severity of liver disease


Professor Jinlin Hou, Institute of Hepatology and Key Lab for Organ Failure Research, Nanfang Hospital, Southern Medical University, No 1838 North Guangzhou Avenue, Guangzhou 510515, China. E-mail:


Summary.  The immune mechanism(s) that lead to hepatitis B-related acute-on-chronic liver failure (HB-ACLF) are poorly understood. Interleukin-21 is a newly discovered cytokine that is involved in autoimmune and inflammatory diseases. Its potential role in HB-ACLF remains unknown. The serum levels of 12 immune cytokines measured by cytometric bead arrays and the frequency of IL-21-secreting CD4+ T cells in peripheral blood mononuclear cells (PBMC) measured by intracellular cytokine staining were compared in moderate chronic hepatitis B (M-CHB, n = 20), severe chronic hepatitis B (S-CHB, n = 20), HB-ACLF (n = 39) and healthy controls (n = 10). PBMC from M-CHB patients or healthy subjects were stimulated with rhIL-21 in vitro, and cytokines in supernatants were measured by FlowCytomix. The frequencies of IL-21-secreting CD4+ T cells were higher in HB-ACLF (both < 0.001) and S-CHB (= 0.002 and 0.001) as compared to M-CHB patients and controls. Serum IL-21 levels were highest (< 0.001) in HB-ACLF and positively associated with high MELD score (= 0.001) and mortality (= 0.038). Recovery from HB-ACLF was associated with reduced serum IL-21 levels (= 0.003) and lower CD4+IL-21+ T-cell frequency (= 0.006). The secretions of IL-1β (< 0.001), IL-6 (< 0.001), IL-10 (< 0.001), IFN-γ (= 0.001) and TNF-α (= 0.042) from PBMC were significantly increased with rhIL-21 stimulation. In summary, IL-21 has a causal role in the development of severe liver inflammation, which is upregulated in HB-ACLF and associated with severity of liver disease.