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.

Regeneration in acute-on-chronic liver failure – the phantom lost its camouflage

“…9 In humans it was demonstrated that lower IL-22BP levels in alcoholic hepatitis were associated with increased mortality. 10 More recently, these results were replicated in a larger cohort of patients with cirrhosis and ACLF, where low IL-22BP/IL-22 ratio and high IL-22 levels were associated with adverse outcome, 11 as IL-22 signalling may not only be pro-regenerative but also induce hepatocellular production of acute-phase proteins, thus augmenting proinflammatory responses. 12 The interaction with IL-22BP will need to be carefully monitored in any prospective human studies.…”

An Open‐Label, Dose‐Escalation Study to Assess the Safety and Efficacy of IL‐22 Agonist F‐652 in Patients With Alcohol‐associated Hepatitis

“…Recently, high levels of IL-22 have been associated with mortality from acute-onchronic liver failure, probably reflecting the severity of the disease. (36) The efficacy of IL-22 in mitigating liver injury induced by alcohol, carbon tetrachloride (CCl 4 ), or a high-fat diet has been demonstrated in animal models. (15,(37)(38)(39)(40) The IL-22 agonist's safety profile and unique biology, which specifically targets epithelial cells, suggests its potential use as monotherapy in patients with AH and MELD scores of 11-28.…”

Reply to: “Interleukin-22 in acute-on-chronic liver failure: A matter of ineffective levels, receptor dysregulation or defective signalling?”

“…Nevertheless, we agree with the hypothesis by Schwarzkopf et al that the ineffective hepatoprotection by endogenous IL-22 in patients with ACLF may be due to high levels of IL-22BP. 1,3 However, the pharmacological treatment with IL-22Fc, which was the focus of our study, caused a several thousand-fold increase in serum IL-22 (~700,000 pg/ml after IL-22Fc vs.~200 pg/ml before IL-22Fc) and great biological responses in healthy volunteers 6,7 to an immunoglobulin constant region (IgG-Fc) and has a long half-life in vivo. 6,7 Such high levels of IL-22Fc can probably overcome the inhibitory function of IL-22BP and ameliorate ACLF by activating the pro-regenerative STAT3 signaling in hepatocytes.…”

“…The first question raised relates to the role of endogenous interleukin (IL)-22 and IL-22 binding protein (IL-22BP) in acuteon-chronic liver failure (ACLF). Serum levels of IL-22 are elevated in patients with ACLF 1 and in mouse models of ACLF induced by infection of adenovirus-CYP4502D6 plus injection of cecal slurry (CS) or chronic CCl 4 plus 2 binges of ethanol. 2 Actually, we also found that serum IL-22 levels were mildly but significantly elevated in our ACLF model, which was illustrated in Fig.…”

“…3 The role of this endogenous IL-22 elevation in ACLF, which was not the focus of our study, remains obscure, although endogenous IL-22 has been shown to protect against acute liver injury 4 and bacterial infection in mice. 5 One enigma is that humans have a thousand-fold higher circulating IL-22BP than mice (~40,000-70,000 pg/ml in humans vs.~40 pg/ml in mice) 1,3 ; the reason for this huge difference is not clear. Although IL-22BP has been shown to inhibit IL-22 signaling, the degree to which IL-22BP inhibits IL-22 signaling remains unclear, and the exact functions of IL-22BP still remain obscure.…”