SUPPRESSION OF LIPOPOLYSACCHARIDE-STIMULATED RELEASE OF TUMOR-NECROSIS-FACTOR BY ADENOSINE - EVIDENCE FOR A(2) RECEPTORS ON RAT KUPFFER CELLS

In liver grafts that will fail as a result of storage injury, reperfus ion activates Kupffer cells. Overproduction of tumor necrosis factor b y activated Kupffer cells may cause primary graft nonfunction, multipl e organ failure and, eventually, death of graft recipients. Carolina r inse solution, adenosine, nisoldipine, pentoxifylline and prostaglandi n E(1) reduce graft failure from storage/reperfusion injury. To test t he hypothesis that these agents act by suppressing cytokine release by activated Kupffer cells, we assessed the effect of each drug on tumor necrosis factor released from cultured rat Kupffer cells stimulated w ith lipopolysaccharide. Adenosine, nisoldipine and prostaglandin E(1) each suppressed lipopolysaccharide-stimulated tumor necrosis factor re lease. The adenosine A(2) receptor agonists. 5-n-ethylcarboxamidadenos ine, 2-chloro-adenosine and R-phenylisopropyl adenosine also blocked t umor necrosis factor release in a potency suggestive of A(2) receptor activity. Xanthine amine congener, a specific A(2) receptor antagonist , failed to reverse the suppression by adenosine of tumor necrosis fac tor release, whereas CGS15943A, an A(2) receptor antagonist, did rever se suppression by adenosine and 5-n-ethylcarboxamidadenosine. CGS15943 A had no effect on suppression of lipopolysaccharide-stimulated tumor necrosis factor release by nisoldipine or prostaglandin E(1). Dibutyry l-cyclicAMP also suppressed tumor necrosis factor release. Adenosine, 5-n-ethylcarboxamidadenosine, prostaglandin E(1) and pentoxifylline in creased cyclicAMP levels in cultured Kupffer cells, but nisoldipine di d not. We conclude that (a) adenosine A(2) receptors exist on Kupffer cells, (b) the suppression of tumor necrosis factor release by adenosi ne occurs by way of a cyclicAMP-dependent adenosine A(2) receptor mech anism, (c) prostaglandin E(1) and nisoldipine also suppress turner nec rosis factor release but do not act through adenosine receptors and (d ) because agents that suppress tumor necrosis factor release by Kupffe r cells also reduce graft failure after liver transplantation, activat ion of Kupffer cells and release of tumor necrosis factor may be invol ved in storage/reperfusion injury to liver grafts.