A Protective Function of IL-22BP in Ischemia Reperfusion and Acetaminophen-Induced Liver Injury

Kleinschmidt, Dörte; Giannou, Anastasios D.; McGee, Heather M.; Kempski, Jan; Steglich, Babett; Huber, Francis; Ernst, Thomas; Shiri, Ahmad Mustafa; Wegscheid, Claudia; Tasika, Elena; Huebener, Peter; Huber, Philipp; Bedke, Tanja; Steffens, Niklas; Agalioti, Theodora; Fuchs, Tobias A.; Noll, Jill; Lotter, Hannelore; Tiegs, Gisa; Lohse, Ansgar W.; Axelrod, Jonathan H.; Galun, Eithan; Flavell, Richard A.; Gagliani, Nicola; Huber, Samuel

doi:10.4049/jimmunol.1700587

Cited by 38 publications

(52 citation statements)

References 54 publications

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“…B). In this regard, STAT3 promotes the well‐described positive effect of IL‐22 on hepatocellular proliferation/survival, whereas STAT1 is rather a proinflammatory transcription factor inducing a large number of proinflammatory mediators and cytokines …”

Section: Resultsmentioning

confidence: 99%

“…However, high serum levels of IL‐22 have been associated with adverse outcomes in patients with alcoholic and nonalcoholic liver disease . Possible explanations for this phenomenon may include unwanted proinflammatory effects of IL‐22, which can augment Th17 immune responses, as well as insufficient biological activity of IL‐22 due to inhibitory mechanisms such as IL‐22BP …”

mentioning

confidence: 99%

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

Schwarzkopf¹,

Rüschenbaum²,

Barat³

et al. 2019

Hepatol Commun

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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.

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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

Schwarzkopf¹,

Rüschenbaum²,

Barat³

et al. 2019

Hepatol Commun

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“…The role of IL-22 is currently being studied with mixed results in APAP hepatotoxicity. Knockout of IL-22 binding protein (IL-22BP) results in increased inflammation and increased liver injury in an IL-22/CXCL10 dependent manner [77]. However, pretreatment with IL-22 reduced injury through STAT3 activation [78].…”

Section: The Acetaminophen-induced Sterile Inflammatory Responsementioning

confidence: 99%

Mechanisms of Inflammatory Liver Injury and Drug-Induced Hepatotoxicity

Woolbright

Jaeschke

2018

Curr Pharmacol Rep

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Purpose of Review This article provides a brief overview of mechanisms of inflammatory liver injury and how this applies to drug hepatotoxicity with a particular emphasis on the role of inflammation in acetaminophen-induced liver injury. Recent Findings Significant progress has been made in the last decade in our understanding of the initiation of sterile inflammation after necrotic cell death by the release of damage-associated molecular patterns and their recognition by toll-like receptors and others on macrophages. These events trigger the formation of cytokines and chemokines directly or with assistance of inflammasome activation thereby activating and recruiting leukocytes including neutrophils and monocyte-derived macrophages into the necrotic areas. Although this sterile inflammatory response is mainly geared towards the removal of necrotic cell debris and preparation of regeneration, there are conditions where these innate immune cells can aggravate the initial injury. The mechanisms and controversial findings of the innate immunity are being discussed in detail. In contrast, drug metabolism and formation of a reactive metabolite that binds to proteins in the absence of extensive cell death, can induce an adaptive immune response, which eventually also results in severe liver injury. However, the initiating event appears to be the formation of protein adducts, which act as haptens to activate an adaptive immune response. Overall, these mechanisms are less well understood. Summary The past decade has revolutionized our understanding of the mechanisms that control the interplay between cell death and innate or adaptive immune responses. This report provides an update on these mechanisms.

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“…Hence, high doses of IL-22 could be required for a therapeutic use of IL-22 in patients with ACLF. Furthermore, IL-22 also has proinflammatory functions that may adversely impact on the outcome of patients with severe liver diseases, and a recent study has revealed a protective role of IL-22BP in a murine model of acute liver failure [46]. Nevertheless, IL-22 appears to be a promising candidate to be investigated for the prevention and treatment of ACLF.…”

Section: Interleukin-22mentioning

confidence: 99%

“…Of note, IL-22 signaling can be prevented by the soluble IL-22 binding protein (IL-22BP) [46]. IL-22 signaling is considered to be protective in chronic liver disease, as it strengthens the intestinal cellular barrier, promotes intestinal immune responses via induction of antimicrobial proteins, and promotes liver regeneration in vitro as well as in animal models [45].…”

Section: Interleukin-22mentioning

confidence: 99%

Immunodysfunction in Acute-on-Chronic Liver Failure

Lange¹,

Moreau²

2018

Visc Med

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Background: Increasing evidence reveals a close and reciprocal link between acute-on-chronic liver failure (ACLF) and immunodysfunction. Methods: A literature search in PubMed and abstract databases of relevant congresses was performed. Results: Important characteristics of liver cirrhosis like tissue hypoxia, cell death, or bacterial translocation maintain a state of chronic inflammation. Precipitating events of ACLF such as infections or alcoholic hepatitis are capable of strongly augmenting cirrhosis-associated systemic inflammation to grades sufficient to induce ACLF-defining organ failures. Chronic systemic inflammation, however, is causally linked to profound immunosuppression. As a consequence, patients with liver cirrhosis and in particular with ACLF are at high risk for severe infections. Promising strategies to ameliorate immunodysfunction, like albumin substitution, administration of recombinant interleukin-22 or granulocyte colony-stimulating factor, antibiotic prophylaxis, or anticoagulation, are under development and offer the chance to specifically prevent and treat ACLF. Conclusion: A better understanding of the immunopathology of ACLF will likely translate into the implementation of specific therapeutic modalities to prevent and overcome ACLF.

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A Protective Function of IL-22BP in Ischemia Reperfusion and Acetaminophen-Induced Liver Injury

Cited by 38 publications

References 54 publications

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

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

Mechanisms of Inflammatory Liver Injury and Drug-Induced Hepatotoxicity

Immunodysfunction in Acute-on-Chronic Liver Failure

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