Preactivation of NKT cells with [alpha]-GalCer protects against hepatic ischemia-reperfusion injury in mouse by a mechanism involving IL-13 and adenosine [A.sub.2A] receptor

Hepatic preconditioning has emerged as a promising strategy of activating natural pathways to augment tolerance to liver ischemia-reperfusion (IR) injury. Liver-resident natural killer T (NKT) cells play an important role in modulating the local immune and inflammatory responses. This work was aimed to investigate whether preactivation of NKT cells could provide a beneficial 'preconditioning' effect to ameliorate the subsequent hepatic IR injury. To selectively activate NKT cells, C57BL/6 mice were treated intraperitoneally with the glycolipid antigen a-galactosylceramide ([alpha]-GalCer) 1 h prior to hepatic ischemia. Significantly reduced liver IR injury was observed in mice pretreated with aGalCer, and this protective effect was specifically abrogated by a CD1d blocking antibody. Serum TNF-[alpha], IFN-[gamma] and IL-13 levels were markedly increased shortly after [alpha]-GalCer injection. Pretreatment with a neutralizing antibody against TNF-[alpha] or IFN-[gamma] did not influence the protective effect of [alpha]-GalCer preconditioning, whereas preadministration of an IL-13 neutralizing antibody completely abolished the effect. Treatment with [alpha]-GalCer also led to an increased expression of adenosine [A.sub.2A] receptor ([A.sub.2A]R) in the liver, and blockade of [A.sub.2A]R by SH58261 diminished [alpha]-GalCer pretreatment-mediated attenuation of liver IR injury. In contrast, administration of the selective [A.sub.2A]R agonist CGS21680 reversed the counteracting effect of the IL-13 neutralizing antibody on [alpha]-GalCer preconditioning. Additionally, [alpha]-GalCer pretreatment was associated with a decreased neutrophil accumulation in the ischemic liver. These findings provide the first evidence that hepatic preconditioning by prcactivation of NKT cells with [alpha]-GalCer protects the liver from IR injury via an IL-13 and adenosine [A.sub.2A]R-dependent mechanism. liver protection; natural killer T cells; glycolipid; Thl/Th2 cytokines; [alpha]-galactosylceramide