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

Abstract

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 P < 0.001) and S-CHB (P = 0.002 and 0.001) as compared to M-CHB patients and controls. Serum IL-21 levels were highest (P < 0.001) in HB-ACLF and positively associated with high MELD score (P = 0.001) and mortality (P = 0.038). Recovery from HB-ACLF was associated with reduced serum IL-21 levels (P = 0.003) and lower CD4+ IL-21(+) T-cell frequency (P = 0.006). The secretions of IL-1β (P < 0.001), IL-6 (P < 0.001), IL-10 (P < 0.001), IFN-γ (P = 0.001) and TNF-α (P = 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.

The Transforming Growth Factor β1/Interleukin-31 Pathway Is Upregulated in Patients with Hepatitis B Virus-Related Acute-on-Chronic Liver Failure and Is Associated with Disease Severity and Survival

“…Therefore, the TGF-␤1/IL-31 pathway may be involved in liver injury by direct inflammatory function and by modulating the expression of other inflammatory cytokines of the innate and adaptive immune cells. We are not sure whether in this study increased expression of TGF-␤1 and IL-31 initially triggered the liver injury in ACLF or was just a part of the inflammatory reaction to the liver injury, but we are certain that high levels of expression of TGF-␤1 and IL-31 as well as other inflammatory cytokines would precipitate and worsen the pathological process of the liver injury, which in turn could facilitate expression of more of those cytokines (28). For instance, IL-21 is an important inflammatory factor and was possibly involved in the liver injury by regulating the function of innate and adaptive immunocompetent cells and/or affecting the expression of other inflammatory cytokines (28).…”

“…Currently, the pathogenesis of liver injury in ACLF remains unclear, but the "three-beat" hypothesis (28), that is, immunolesion, hypoxic ischemia, and endotoxemia, may explain the progressive liver injury and malfunction of this organ. Previous studies have focused on the first "beat," and they suggest that natural killer (NK) cells (29), Kupffer cells (30), dendritic cells (DCs) (24), monocytes, Th1 cells (30), Th17 cells (23,31), regulatory T (Treg) cells (21), and other immunologically relevant cells are all involved in the pathogenesis of liver injury in ACLF.…”

Role of interleukin-21 in HBV infection: friend or foe?

“…In vitro, IL-21 could upregulate the expression of the pro-inflammatory cytokines IL-1b, IL-6 and TNF-a in peripheral blood mononuclear cell from both healthy subjects and CHB patients. 47 These results suggest that IL-21may have a causal role in the development of severe liver inflammation. However, there was no correlation between serum IL-21 and ALT levels in this study, which is in agreement with our subsequent finding from immune activated CHB patients; 22 therefore, IL-21 production may be related to the immune response to HBV, rather than to the degree of liver inflammation.…”

“…47 Moreover, a high level of serum IL-21 was identified to be positively associated with increased model for end-stage liver disease score and mortality. In vitro, IL-21 could upregulate the expression of the pro-inflammatory cytokines IL-1b, IL-6 and TNF-a in peripheral blood mononuclear cell from both healthy subjects and CHB patients.…”

“…Since patients with IFN-a treatment have relatively higher rates of HBeAg seroconversion, it will be interesting to investigate whether the Tfh/IL-21/B cells axis plays an important 21,23 (c) Aberrant IL-21 derived from Th17 cells (perhaps Tfh cells) can upregulate the expression of the pro-inflammatory cytokines IL-1b, IL-6 and TNF-a in PBMC from CHB patients, resulting in immune-mediated liver injury and inflammation. [46][47][48] (d) IL-21 contributes to the severity of disease progression through HSC activation, and might be involved in the process of liver fibrogenesis. [49][50][51] Currently, little information is known regarding the immune effects of IL-21 on NK or NKT cells in the context of HBV infection.…”