In this review the hypothesis is developed, that high concentrations of adenosine are anti-inflammatory and therefore beneficial in inflammatory disease like rheumatoid arthritis. The anti-inflammatory effect of adenosine is mediated mainly via specific adenosine receptors on immune cells that are involved in the disease process. Unfortunately, at least three mechanisms support a decrease in the local concentration of adenosine at the site of inflammation: 1) A decrease in sympathetic innervation, which leads to decreased local release of the cotransmitter ATP at the site of inflammation and therefore to a decreased level of its degradation product adenosine. 2) High activities of the adenosine degrading enzyme adenosine deaminase, which leads to increased degradation of adenosine to inosine and therefore decreases the concentration of adenosine 3) Lower activity of the ATP degrading enzyme 5-Ecto-nucleotidase, which leads to a slower degradation of ATP to adenosine, also resulting in lower local levels of adenosine present. Therefore, it has to be considered that the optimal treatment for rheumatoid arthritis has to include drugs that specifically target adenosine receptors or the adenosine metabolism to increase local adenosine concentrations. In this respect the mechanism of action of low-dose methotrexate therapy is discussed, which is thought to involve the inhibition of adenosine degrading enzymes rather than antiproliferative effects.
Keywords: Adenosine, neuroimmunology, rheumatoid arthritis, sympathetic nervous system
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