Pretreatment with Interleukin-33 Reduces Warm Hepatic Ischemia/Reperfusion Injury in Mice

BACKGROUND: Interleukin (IL)-33 is a recently identified member of the IL-1 family that binds to the receptor, ST2L. This study examined IL-33 production in mouse liver and investigated its role in hepatic ischemia/reperfusion (I/R) injury. METHODS: Male BALB/c mice ((22 ± 3) g) were subjected to 90 minutes partial hepatic ischemia, followed by 6 hours reperfusion. First, mice were randomized into two groups: control group (laparotomy only, without blocking blood supply) and ischemia model group. IL-33 mRNA and serum protein levels were measured at 30, 60, 90 minutes after ischemia and 2 and 6 hours after reperfusion. Second, mice were randomized into four groups: control, model (injection of rabbit IgG polyclonal antibody), recombinant IL-33 intervention and anti-ST2L antibody intervention group. Mice were sacrificed 6 hours after reperfusion. Liver pathology was observed via transmission electron microscopy. Serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), IL-4, IL-5, IL-13, interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) levels were measured. RESULTS: Levels of IL-33 mRNA and protein did not change during ischemia (P > 0.05) but increased significantly during reperfusion (P < 0.05). After reperfusion for 6 hours, serum levels of ALT, AST, IL-4, IL-5, IL-13, IFN-γ and TNF-α were significantly increased (P < 0.05), and hepatocellular ultrastructure was damaged. Pretreatment with IL-33 attenuated severity of liver damage compared with controls, but pretreatment with anti-ST2L antibody increased severity. Serum levels of IL-4, IL-5 and IL-13 protein increased whereas IFN-γ decreased following IL-33 pretreatment. Pretreatment with anti-ST2L antibody significantly decreased serum IL-4, IL-5, IL-13 levels and increased serum IFN-γ levels compared with controls (P < 0.05). There was no change in the level of TNF-α. CONCLUSION: IL-33 is produced systematically and locally in liver during I/R injury. Pretreatment with IL-33 is therapeutic for hepatic I/R injury, possibly via inducing a Th1 to Th2 shift.