Endogenous IL-13 protects hepatocytes and vascular endothelial cells during ischemia/reperfusion injury

Abstract

Hepatic ischemia/reperfusion injury involves a complex inflammatory cascade resulting in neutrophil-mediated injury of hepatocytes. Previous studies from our laboratory have established that exogenous administration of the anti-inflammatory cytokines interleukin 10 (IL-10) and IL-13 can ameliorate the inflammatory response and significantly reduce hepatocellular injury. The purpose of the present study was to determine if IL-10 and IL-13 function as endogenous regulators of the hepatic inflammatory response to ischemia/reperfusion. Wild-type, IL-10–, and IL-13–deficient (IL-10 −/−, IL-13 −/−) mice were exposed to 90 minutes of partial hepatic ischemia and up to 24 hours of reperfusion. In wild-type mice, expression of IL-10 and IL-13 shared similar expression profiles with maximal production after 8 hours of reperfusion. There were no significant differences between wild-type and IL-10 −/− mice in response to hepatic ischemia and reperfusion. IL-13 −/− mice had much greater liver injury, as assessed biochemically and histologically, than wild-type mice. There were no differences between wild-type and IL-13 −/− mice in their production of inflammatory cytokines, but IL-13 −/− mice displayed disrupted neutrophil accumulation, with less neutrophils present in the hepatic parenchyma and far more neutrophils adherent to the endothelium of large hepatic venules than wild-type mice. These observations were associated with increased liver endothelial cell injury in IL-13 −/− mice, as measured by serum levels of hyaluronic acid. In vitro, IL-13 protected hepatocytes from H 2O 2-induced cytotoxicity. In conclusion, IL-10 is not an important endogenous regulator of the inflammatory response to hepatic ischemia/reperfusion. In contrast, endogenous IL-13 appears to be critical for the control of this response, with prominent protective effects on hepatocytes and hepatic endothelial cells. (H EPATOLOGY 2003;37:304-312.)