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Inotek Corp., Beverly, MA 01915
Extracellular purines, including adenosine and ATP, are potent
endogenous immunomodulatory 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 affect inflammatory/immune processes.
In immunostimulated macrophages and spleen cells, inosine potently
inhibited the production of the proinflammatory cytokines TNF-
,
IL-1, IL-12, macrophage-inflammatory protein-1, and IFN-
, but
failed to alter the production of the anti-inflammatory cytokine
IL-10. The effect of inosine did not require cellular uptake by
nucleoside transporters and was partially reversed by blockade of
adenosine A1 and A2 receptors. Inosine
inhibited cytokine production by a posttranscriptional mechanism. The
activity of inosine was independent of activation of the p38 and
p42/p44 mitogen-activated protein kinases, the phosphorylation of the
c-Jun terminal kinase, the degradation of inhibitory factor 
B, and
elevation of intracellular cAMP. Inosine suppressed proinflammatory
cytokine production and mortality in a mouse endotoxemic model. Taken
together, inosine has multiple anti-inflammatory effects. These
findings, coupled with the fact that inosine has very low toxicity,
suggest that this agent may be useful in the treatment of
inflammatory/ischemic diseases.
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