[Activity of adenosine in relation to tumor necrosis factor (TNF). Therapeutic outlook]

At physiological and pharmacological doses, adenosine protects tissues against a varieties of injuries: ischemia-reperfusion, convulsions, inflammation.... We tested the hypothesis that the antiinflammatory properties of adenosine occur via a down-regulation of TNF. Agonists of adenosine receptors (ARA) and agents potentiating endogenous adenosine (APA) were evaluated for their effects on TNF production by endotoxin-stimulated human monocytes. Additionally, one of the most potent agonists, R-phenylisopropyladenosine (R-PIA), was tested on two experimental models of acute phase response, endotoxin shock and carrageenan-induced plantar oedema. Several ARA and APA inhibited monocyte TNF production in a concentration-dependent manner. R-PIA and other ARA were active at micromolar concentrations. The property is pharmacologically relevant since rats receiving a lethal dose of endotoxins were protected by R-PIA and endotoxin-induced serum TNF levels were abolished by a pretreatment with R-PIA. Inhibitory effects on serum TNF production were obtained with similar doses of dexamethasone sodium phosphate and one hundred-fold higher doses of pentoxifylline. R-PIA was also found active on carrageenan-induced oedema. The anti-oedematous properties of R-PIA were associated with a marked reduction of locally-produced TNF and were also observed after the administration of dexamethasone, pentoxifylline and a neutralizing anti-TNF antibody. Our results indicate that adenosine is a potent inhibitor of TNF production induced by different stimuli. This property could lead to therapeutic applications in inflammatory diseases and other in which TNF is known to play a pathogenic or aggravating role. Comparison between ARA and APA in terms of tolerance and efficacy merits further attention.