Therapy with interleukin-22 alleviates hepatic injury and hemostasis dysregulation in rat model of acute liver failure.

Tariq Helal Ashour

doi:10.1155/2014/705290

Abstract

The therapeutic efficacy of interleukin-22 (IL-22) on liver injury and hematological disturbances was studied in rat model of acute liver failure (ALF) induced by D-galactosamine/lipopolysaccharide (D-GalN/LPS). The following parameters were investigated: (1) survival rate, (2) serum levels of liver function enzymes (aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP)), total bilirubin (TBILI), and total albumen (ALB), (3) blood clotting tests (prothrombin time (PT), activated partial thromboplastin time (aPTT), and fibrinogen level (FIB)) and white blood cells (WBCs), red blood cells (RBCs), and platelet counts, (4) hepatic levels of tumor necrosis factor-α (TNF-α) and cyclooxygenase-2 (COX-2), and (5) liver histopathology. After 48 hours of D-GalN/LPS, the rats exhibited 20% mortality, significant increases in AST, ALT, ALP, TBILI, PT, and aPTT, TNF-α, and COX-2 and significant decreases in FIB, WBCs, and RBCs. By contrast, therapy with IL-22 prevented the lethal effect of D-GalN/LPS by 100% and efficiently alleviated all the biochemical and hematological abnormalities that were observed in ALF untreated group. Furthermore, IL-22 treatment decreased the hepatic contents of TNF-α and COX-2. The histopathological findings also supported the hepatoprotective effect of IL-22. Taken together, therapy with IL-22 can represent a promising therapeutic tool against liver injury and its associated hemostasis disturbances.

Highlights

Acute liver failure (ALF) and fulminant hepatitis (FH) are devastating liver diseases with multiple etiologies, coagulability dysfunctions, poor prognosis, and 90% overall mortality rate [1]
IL-22 exerts its biological functions via activation of membrane-bound heterodimeric receptor complex consisting of IL-22R1 and IL-10R2, which is predominantly expressed by epithelial cells including gut and liver cells [4, 5]
Commercial enzyme-linked immunosorbent assay (ELISA) kits of rat COX-2 rat tumor necrosis factor-α (TNF-α) were purchased from R&D Systems and IBL International (GmbH, Hamburg, Germany), respectively

Summary

Introduction

Acute liver failure (ALF) and fulminant hepatitis (FH) are devastating liver diseases with multiple etiologies, coagulability dysfunctions, poor prognosis, and 90% overall mortality rate [1]. Up till there are no effective treatment therapies for this disease and its highly fatal complications [2]. Development of more effective and highly selective therapeutic strategy is a paramount medical need. IL-22 exerts its biological functions via activation of membrane-bound heterodimeric receptor complex consisting of IL-22R1 and IL-10R2, which is predominantly expressed by epithelial cells including gut and liver cells [4, 5]. In addition to its defense role against infectious pathogens, numerous studies demonstrated the favorable tissue protective properties of either exogenously administered or endogenously overexpressed IL-22. In this concept, hepatocytes abundantly express IL-22R and its stimulation via IL-22 promotes hepatocyte growth and survival [5]

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