Abstract
NKT cells play a key role in initiating an inflammatory cascade during liver ischemia/reperfusion injury (IRI). Cytokine production by NKT cells is inhibited by A2A adenosine receptor (A2AAR) activation. To further investigate the mechanism of A2AAR-mediated liver protection, we selectively activated NKT cells in vivo with α-galactosylceramide (α-GalCer, 4 μg/mouse) a glycolipid that is presented by CD1d to invariant NKT cell receptors. Liver injury and lymphocyte activation were assessed by measuring serum alanine transaminase (ALT) which peaked in 18 h, and proinflammatory cytokines in various cells by FACS. Mice treated with the selective A2AAR agonist ATL313 (1 ng/kg/min) prior to and during α-GalCer treatment had significantly reduced serum ALT and interferon (IFN)- 1 _ levels. In NKT cells, ATL313 reduced intracellular IFN-γ, TNF-α and IL-2 by 30–60%. Peak IFN-γ production occurred earlier (< 2 hr) in NKT cells than in NK cells (> 4 hr) suggesting that NK cell activation is downstream of NKT cell activation. All of the effects of ATL313 were abolished in A2AAR KO mice. In IFN-γ KO mice there was a 58% and 70% reduction in TNF-α and IL-2, respectively in response to α-GalCer, suggesting a primary role by IFN-γ in triggering a cytokine cascades that drives liver injury. In summery, selective NKT cell-activation by α-GalCer causes liver injury which is reduced by the A2AAR activation. It appears that ATL313 exerts its action on NKT and possibly other lymphocytes primarily by limiting IFN-γ production from these cells during early inflammatory processes.
Supported by NIH R01 HL37942
