Interleukin-1 receptor antagonist expression is inversely associated with outcomes of hepatitis B-related acute-on-chronic liver failure

Abstract

Interleukin-1 receptor antagonist (IL-1ra) is a naturally occurring anti-inflammatory antagonist of the proinflammatory cytokine IL-1, a critical factor in many inflammatory diseases. The aim of the present study was to investigate the role of IL-1ra in hepatitis B-related acute-on-chronic liver failure (HB-ACLF). Serum cytokine concentrations were measured using a Q-Plex array in 31 patients with HB-ACLF, 28 patients with acute hepatitis B (AHB), 31 patients with chronic hepatitis B (CHB) and 15 healthy control patients (HCs). Additionally, peripheral blood mononuclear cells (PBMCs) from patients with HB-ACLF were incubated with PBS or lipopolysaccharide and/or different concentrations of recombinant human IL-1ra (rhIL-1ra) in vitro. Cytokines in the supernatant were measured using a Q-Plex array. The median serum IL-1ra level in patients with HB-ACLF was 186.46 (350.22) pg/ml, which was significantly higher than all other groups (AHB, P=0.012; CHB, P<0.001; HCs, P<0.001). However, the ratio of IL-1ra/IL-1β was significantly lower in the HB-ACLF group compared with the AHB group (P=0.048). Median serum IL-1ra levels in patients with AHB were also significantly increased compared with those in the CHB (P<0.001) and HC (P<0.001) groups. Patients who succumbed to mortality within 3 months of the study were found to have significantly lower IL-1ra concentrations (P=0.02) and IL-1ra/IL-1β ratios (P=0.007) compared with surviving patients with HB-ACLF. Furthermore, serum IL-1ra concentrations were negatively associated with the Model for End-stage Liver Disease score (r=−0.870; P<0.001). Cytokine secretion by PBMCs in vitro was significantly inhibited in a dose-dependent manner by rhIL-1ra (125–500 ng/ml; all P<0.05). These results suggest that IL-1ra is associated with the development of liver inflammation, which is reduced in patients with HB-ACLF and inversely associated with disease severity.

Serum Interleukins as Potential Prognostic Biomarkers in HBV-Related Acute-on-Chronic Liver Failure

“…IL-1 plays a key role in immune response and inflammation. Interleukin-1 receptor antagonist (IL-1RA) is a natural anti-inflammatory antagonist of IL-1, induces the expression of anti-inflammatory cytokines (like IL-10 and IL-4), and reduces the production of proinflammatory cytokines (like IFN- γ , IL-1, and IL-6) [ 17 ], reducing inflammation through competitive inhibition without triggering signaling cascades [ 18 ]. Imbalance of IL-1RA and IL-1 lead to the progression of various diseases [ 19 ].…”

“…IL-1RA also owns an antiapoptotic effect in acute and chronic inflammation and can facilitate the proliferation of liver cell [ 21 ]. Serum IL-1RA concentration was negatively correlated with the end-stage liver disease score model, IL-1RA concentration, and IL-1RA/IL-1 β ratio of HBV-ACLF patients in the death group was pronouncedly lower than those in the survival group [ 17 ]. This indicates that IL-1RA is vital in liver inflammation, and liver inflammation is relatively decreased in patients with HBV-ACLF, which is negatively correlated with the severity of the disease [ 17 ].…”

“…It was found that levels of serum IL-1RA, IL-1 β , IL-6, and TNF- α in patients with acute hepatitis B (AHB) and chronic hepatitis B (CHB) were lower compared to patients with HBV-ACLF [ 20 , 22 ]. The ratio of IL-1RA to IL-1 β was lower in the HBV-ACLF group compared with the AHB group [ 22 ], and the IL-1RA concentration and IL-1RA/IL-1 β ratio of the death group were significantly lower than those of the survival group [ 22 ], but IL-1RA/IL-1 β were higher, suggesting that endogenous IL-1RA alone was not enough to counter the action of IL-1, leading to cascade inflammation and liver injury [ 17 ], and the serum IL-1RA concentration was negatively correlated with the MELD score [ 22 ]. Studies have found that the serum IL-1RA level of female ACLF patients is obviously higher than that of males [ 17 ], and the IL-1RA produced by peripheral monocytes obtained from the female is 5-10 times that of male cells during the menstrual cycle [ 19 ].…”