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J Immunol. 2017 Dec 15;199(12):4078-4090. doi: 10.4049/jimmunol.1700587. Epub 2017 Nov 6.

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

Author information

1
I. Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
2
Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
3
Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
4
Department and Clinic for Diagnostic and Interventional Radiology and Nuclear Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
5
Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
6
Institute of Clinical Chemistry and Central Laboratories, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
7
Bernhard Nocht Institute for Tropical Medicine, 20359 Hamburg, Germany.
8
Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem 91120, Israel.
9
Department of Immunobiology, School of Medicine, Yale University, New Haven, CT 06520.
10
Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06520; and.
11
Immunology and Allergy Unit, Department of Medicine Solna, Karolinska Institute, 17176 Stockholm, Sweden.
12
I. Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; shuber@uke.de.

Abstract

Acute liver injury can be secondary to a variety of causes, including infections, intoxication, and ischemia. All of these insults induce hepatocyte death and subsequent inflammation, which can make acute liver injury a life-threatening event. IL-22 is a dual natured cytokine which has context-dependent protective and pathogenic properties during tissue damage. Accordingly, IL-22 was shown to promote liver regeneration upon acute liver damage. However, other studies suggest pathogenic properties of IL-22 during chronic liver injury. IL-22 binding protein (IL-22BP, IL-22Ra2) is a soluble inhibitor of IL-22 that regulates IL-22 activity. However, the significance of endogenous IL-22BP in acute liver injury is unknown. We hypothesized that IL-22BP may play a role in acute liver injury. To test this hypothesis, we used Il22bp-deficient mice and murine models of acute liver damage induced by ischemia reperfusion and N-acetyl-p-aminophenol (acetaminophen) administration. We found that Il22bp-deficient mice were more susceptible to acute liver damage in both models. We used Il22 × Il22bp double-deficient mice to show that this effect is indeed due to uncontrolled IL-22 activity. We could demonstrate mechanistically increased expression of Cxcl10 by hepatocytes, and consequently increased infiltration of inflammatory CD11b+Ly6C+ monocytes into the liver in Il22bp-deficient mice upon liver damage. Accordingly, neutralization of CXCL10 reversed the increased disease susceptibility of Il22bp-deficient mice. In conclusion, our data indicate that IL-22BP plays a protective role in acute liver damage, via controlling IL-22-induced Cxcl10 expression.

PMID:
29109123
DOI:
10.4049/jimmunol.1700587
[Indexed for MEDLINE]
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