190 AST-120 (SPHERICAL CARBON ADSORBENT) IN COVERT HEPATIC ENCEPHALOPATHY: RESULTS OF THE ASTUTE TRIAL

Abstract

fold; p,0.001 increase in protein secretion following a 2h or 4h stimulation, respectively. The upregulation of IL-6 expression by adenosine was inhibited by the non-specific adenosine receptor antagonist, CGS-15943. Semi-quantitative RT-PCR experiments demonstrated that A2b was the primary adenosine receptor expressed by H69 cells, and expression of A2b protein was confirmed by confocal immunofluorescence. Thus, we directly tested the role of A2b in IL-6 upregulation using pharmacologic and molecular methods. The specific A2b receptor antagonist MRS-1754 completely blocked adenosine-sensitive IL-6 upregulation; moreover, H69 cells transfected with A2b-specific siRNA, but not an siRNA control, did not upregulate IL-6 in response to adenosine. Since A2b receptors are known to be Gscoupled, we demonstrated that adenosine induced an upregulation of cAMP (6.6-fold; p,0.001). In summary, adenosine, acting via the A2b receptor, activates cholangiocyte IL6 release. Since IL-6 is a critical survival signal, we propose that this signaling pathway is important in the maintenance of liver survival in injury. 1. Cressman, D.E., et al., Liver failure and defective hepatocyte regeneration in interleukin-6-deficient mice. Science, 1996. 274(5291): p. 1379-83. 2. Ezure, T., et al., The development and compensation of biliary cirrhosis in interleukin-6-deficient mice. Am J Pathol, 2000. 156(5): p. 1627-39. 3. Chan, E.S., et al., Adenosine A(2A) receptors play a role in the pathogenesis of hepatic cirrhosis. Br J Pharmacol, 2006. 148(8): p. 1144-55. 4. Chouker, A., et al., In Vivo Hypoxic Preconditioning Protects From Warm Liver Ischemia-Reperfusion Injury Through the Adenosine A2B Receptor. Transplantation, 2012. 94(9): p. 894-902.