Ischemia reperfusion injury results from tissue damage during ischemia and ongoing inflammation and injury during reperfusion. Liver reperfusion injury is reduced by lymphocyte depletion or activation of adenosine A 2A receptors (A 2A Rs) with the selective agonist 4- {3-6-amino-9-(5-ethylcarbamoyl-3,4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl- prop-2-ynyl}-cyclohexanecarboxylic acid methyl ester (ATL146e). We show that NKT cells are stimulated to produce interferon (IFN)-γ by 2 h after the initiation of reperfusion, and the use of antibodies to deplete NK1.1-positive cells (NK and NKT) or to block CD1d-mediated glycolipid presentation to NKT cells replicates, but is not additive to, the protection afforded by ATL146e, as assessed by serum alanine aminotransferase elevation, histological necrosis, neutrophil accumulation, and serum IFN-γ elevation. Reduced reperfusion injury observed in RAG-1 knockout (KO) mice is restored to the wild-type (WT) level by adoptive transfer of NKT cells purified from WT or A 2A R KO mice but not IFN-γ KO mice. Additionally, animals with transferred A 2A R −/− NKT cells are not protected from hepatic reperfusion injury by ATL146e. In vitro, ATL146e potently inhibits both anti-CD3 and α-galactosylceramide–triggered production of IFN-γ by NKT cells. These findings suggest that hepatic reperfusion injury is initiated by the CD1d-dependent activation of NKT cells, and the activation of these cells is inhibited by A 2A R activation. Footnotes Abbreviations used: 8-SPT, 8-sulfophenyltheophylline; α-Gal-Cer, α-galactosylceramide; ADA, adenosine deaminase; ALT, alanine aminotransferase; ANOVA, analysis of variance; A 2A R, adenosine A 2A receptor; ATL146e, 4-{3-6-amino-9- (5-ethylcarbamoyl-3,4-dihydroxy- tetrahydro-furan-2-yl)-9H- purin-2-yl-prop-2-ynyl}- cyclohexanecarboxylic acid methyl ester; H&E, hematoxylin and eosin; IRI, ischemia reperfusion injury; iNKT, invariant NKT; ROS, reactive oxygen species; ZM241385, 4-(2-7-amino-2-2-furyl1,2,4 triazolo2,3- a 1,3,5triazin-5-yl- aminoethyl)phenol. Submitted: 22 May 2006 Accepted: 10 October 2006
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Adenosine A2A receptor activation reduces hepatic ischemia reperfusion injury by inhibiting CD1d-dependent NKT cell activation
Lappas, Courtney M.; Day, Yuan-Ji; Marshall, Melissa A.; Engelhard, Victor H.; Linden, Joel
Follow The Journal of Experimental Medicine
, Volume 203 (12): 2639
Rockefeller University Press – Nov 27, 2006
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