Inosine inhibits inflammatory cytokine production by a posttranscriptionalmechanism and protects against endotoxin-induced shock

Extracellular purines, including adenosine and ATP, are potent endogenous i mmunomodulatory molecules, Inosine, a degradation product of these purines, can reach high concentrations in the extracellular space under conditions associated with cellular metabolic stress such as inflammation or ischemia, In the present study, we investigated whether extracellular inosine can af fect inflammatory/immune processes. In immunostimulated macrophages and spl een cells, inosine potently inhibited the production of the proinflammatory cytokines TNF-alpha, IL-1, IL-12, macrophage-inflammatory protein-1 alpha, and IFN-gamma, but failed to alter the production of the anti-inflammatory cytokine IL-10. The effect of inosine did not require cellular uptake by n ucleoside transporters and was partially reversed by blockade of adenosine A, and A, receptors, Inosine inhibited cytokine production by a posttranscr iptional mechanism. The activity of inosine was independent of activation o f the p38 and p42/p44 mitogen-activated protein kinases, the phosphorylatio n of the c-Jun terminal kinase, the degradation of inhibitory factor kappa B, and elevation of intracellular cAMP, Inosine suppressed proinflammatory cytokine production and mortality in a mouse endotoxemic model. Taken toget her, inosine has multiple anti-inflammatory effects. These findings, couple d with the fact that inosine has very low toxicity, suggest that this agent may be useful in the treatment of inflammatory/ischemic diseases.