title: Preactivation of NKT cells with alpha-GalCer protects against hepatic ischemia-reperfusion injury in mouse by a mechanism involving IL-13 and adenosine A2A receptor.
abstract: 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 alpha-galactosylceramide (alpha-GalCer) 1 h prior to hepatic ischemia. Significantly reduced liver IR injury was observed in mice pretreated with alpha- GalCer, 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 A2A receptor (A2AR) in the liver, and blockade of A2AR by SH58261 diminished alpha-GalCer pretreatment-mediated attenuation of liver IR injury. In contrast, administration of the selective A2AR 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 preactivation of NKT cells with alpha-GalCer protects the liver from IR injury via an IL-13 and adenosine A2AR-dependent mechanism.
authors: Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA.
authors: Zongxian
authors: Z
authors: Cao
authors: Youzhong
authors: Y
authors: Yuan
authors: Geetha
authors: G
authors: Jeyabalan
authors: Qiang
authors: Q
authors: Du
authors: Allan
authors: A
authors: Tsung
authors: David A
authors: DA
authors: Geller
authors: Timothy R
authors: TR
authors: Billiar
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005699:Galactosylceramides / Q000008:administration & dosage / Q000494:pharmacology*; D007274:Injections, Intraperitoneal; D007371:Interferon-gamma / Q000097:blood; D018793:Interleukin-13 / Q000097:blood*; D007511:Ischemia / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000098:blood supply / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008213:Lymphocyte Activation / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D055611:Natural Killer T-Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D020556:Neutrophil Infiltration / Q000187:drug effects; D043705:Receptor, Adenosine A2A / Q000187:drug effects* / Q000378:metabolism; D015427:Reperfusion Injury / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D005699:Galactosylceramides; D018793:Interleukin-13; D043705:Receptor, Adenosine A2A; D014409:Tumor Necrosis Factor-alpha; C493154:alpha-galactosylceramide; D007371:Interferon-gamma