Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 203, Issue 12, Pages 2639-2648Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20061097
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Funding
- NHLBI NIH HHS [R01 HL37942, R01 HL037942] Funding Source: Medline
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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)-gamma 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-gamma 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-gamma. 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 alpha-galactosylceramide-triggered production of IFN-alpha. 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.
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