DIFFERENTIAL REGULATORY EFFECTS OF ADENOSINE ON CYTOKINE RELEASE BY ACTIVATED HUMAN MONOCYTES

Adenosine is an endogenous nucleoside that can modulate the function o f cells involved in the inflammatory response, such as polymorphonucle ar leukocytes (PMN) and monocytes. Production and release of cytokines by activated mononuclear phagocytes is an important event in the path ogenesis of ischemia-reperfusion injury, a pathologic phenomenon that is associated with excessive ATP catabolism and subsequent local relea se of adenosine. The ''retaliatory'' metabolite adenosine has been sho wn to interfere with PMN function, thereby attenuating the deleterious consequences of ischemia and reperfusion. In this study, we demonstra te that adenosine inhibits the production of TNF-alpha, IL-6, and IL-8 by LPS-activated human monocytes with a differential potency. The A(2 ) receptor-specific adenosine analogues 2-chloroadenosine and 5' N-eth ylcarboxamidoadenosine (NECA) were most effective in attenuating LPS-i nduced cytokine production, whereas the A(1)-selective adenosine analo gue N-6-cyclopentyladenosine (CPA) was less effective, indicating that inhibition of cytokine production by adenosine is primarily an A(2) r eceptor-mediated event. The observed inhibitory effects were not restr icted to endotoxin-induced cytokine production, because adenosine also inhibited TNF-alpha production by monocytes stimulated with the proin flammatory cytokine IL-1 beta. Again, 2-chloroadenosine and NECA reduc ed IL-beta-induced TNF-alpha production more potently than CPA. in con trast, adenosine enhanced production of IL-6 and IL-8 by monocytes sti mulated with IL-1 beta Furthermore, only 2-chloroadenosine, but not NE CA, strongly inhibited cytokine-induced IL-6 and IL-8 production. Thes e results suggest an additional A(6) receptor-mediated mechanism of re taliatory action of adenosine under pathologic conditions where cytoki ne production by activated mononuclear phagocytes is involved, such as ischemia-reperfusion injury and septic shock.