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This Article Full Text Full Text (PDF) All Versions of this Article: 297/2/G249    most recent 00041.2009v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Cao, Z. Articles by Billiar, T. R. PubMed PubMed Citation Articles by Cao, Z. Articles by Billiar, T. R.

LIVER AND BILIARY TRACT

Preactivation of NKT cells with -GalCer protects against hepatic ischemia-reperfusion injury in mouse by a mechanism involving IL-13 and adenosine A_2A receptor

Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania

Submitted 3 February 2009 ; accepted in final form 16 June 2009

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 -galactosylceramide (-GalCer) 1 h prior to hepatic ischemia. Significantly reduced liver IR injury was observed in mice pretreated with - GalCer, and this protective effect was specifically abrogated by a CD1d blocking antibody. Serum TNF-, IFN-, and IL-13 levels were markedly increased shortly after -GalCer injection. Pretreatment with a neutralizing antibody against TNF- or IFN- did not influence the protective effect of -GalCer preconditioning, whereas preadministration of an IL-13 neutralizing antibody completely abolished the effect. Treatment with -GalCer also led to an increased expression of adenosine A_2A receptor (A_2AR) in the liver, and blockade of A_2AR by SH58261 diminished -GalCer pretreatment-mediated attenuation of liver IR injury. In contrast, administration of the selective A_2AR agonist CGS21680 reversed the counteracting effect of the IL-13 neutralizing antibody on -GalCer preconditioning. Additionally, -GalCer pretreatment was associated with a decreased neutrophil accumulation in the ischemic liver. These findings provide the first evidence that hepatic preconditioning by preactivation of NKT cells with -GalCer protects the liver from IR injury via an IL-13 and adenosine A_2AR-dependent mechanism.

liver protection; natural killer T cells; glycolipid; Th1/Th2 cytokines; -galactosylceramide