IL-22 and IL-22-Binding Protein Are Associated With Development of and Mortality From Acute-on-Chronic Liver Failure

Abstract

Interleukin-22 (IL-22) has context-dependent hepatoprotective or adverse properties in vitro and in animal models. IL-22 binding protein (IL-22BP) is a soluble inhibitor of IL-22 signaling. The role of IL-22 and IL-22BP in patients with acute-on-chronic liver failure (ACLF) is unclear. Beginning in August 2013, patients with liver cirrhosis with and without ACLF were prospectively enrolled and followed at predefined time points. IL-22 and IL-22BP concentrations were quantified and associated with clinical endpoints. The impact of IL-22BP on hepatocellular IL-22 signaling was assessed by functional experiments. A total of 139 patients were analyzed, including 45 (32%), 52 (37%), and 42 (30%) patients with compensated/stable decompensated liver cirrhosis, acute decompensation of liver cirrhosis, and ACLF at baseline, respectively. Serum levels of IL-22 and IL-22BP were strongly associated with the presence of, or progression to, ACLF (P < 0.001), and with mortality (P < 0.01). Importantly, the mean IL-22BP levels exceeded IL-22 levels more than 300-fold. Furthermore, IL-22BP/IL-22 ratios were lowest in patients with adverse outcomes (i.e., ACLF and death). In vitro experiments showed that IL-22BP at these concentrations inhibits hepatocellular IL-22 signaling, including the induction of acute-phase proteins. The capacity of patient serum to induce signal transducer and activator of transcription 3 phosphorylation was substantially higher in the presence of low versus high IL-22BP/IL-22 ratios. Conclusion: Our study reveals that high IL-22 levels and low ratios of IL-22BP/IL-22 are associated with ACLF and mortality of patients with cirrhosis. Excessive secretion of IL-22BP can neutralize IL-22 in vitro and may prevent—likely in a context-specific manner—hepatoprotective, but also adverse effects, of IL-22 in patients with cirrhosis.