Adenosine receptor activation ameliorates type 1 diabetes

Abstract

Growing evidence indicates that adenosine receptors could be promising therapeutic targets in autoimmune diseases. Here we studied the role of adenosine receptors in controlling the course of type 1 diabetes. Diabetes in CD‐1 mice was induced by multi‐ple‐low‐dose‐streptozotocin (MLDS) treatment and in nonobese diabetic (NOD) mice by cyclophosphamide injection. The nonselective adenosine receptor agonist 5′‐N‐ethylcarboxamidoadenosine (NECA) prevented diabetes development in both MLDS‐challenged mice and in cyclophosphamide‐treated NOD mice. The effect of NECA was reversed by the selective A 2B receptor antagonist N‐(4‐cyanophenyl)‐2‐[4‐(2,3,6,7‐tetrahydro‐2,6‐dioxo‐1,3‐dipropyl‐1H‐purin‐8‐yl)phenoxy]acetamide (MRS 1754). The selective A 1 receptor agonist 2‐chloro‐ N 6 ‐cyclopentyladenosine (CCPA) and A 3 receptor agonist N 6 ‐(3‐iodobenzyl)‐adenosine‐5′‐N‐methylu‐ronamide (IB‐MECA) were less efficacious in ameliorating the course of diabetes. NECA inhibited diabetes in A 2A receptor KO mice and the selective A 2A receptor agonist 2‐ P ‐(2‐carboxyethyl)phenethyl‐amino‐5′‐N‐ethyl‐carboxamidoadenosine (CGS21680) had no effect in normal mice, indicating a lack of role of A 2A receptors. NECA failed to prevent cytokine‐induced β‐cell death in vitro , but NECA strongly suppressed expression of the proinflammatory cytokines TNF‐α, MIP‐1α, IL‐12, and IFN‐γ in pancreata, endotoxin, or anti‐CD3‐stimulated splenic cells, and T helper 1 lymphocytes, indicating that the beneficial effect of NECA was due to immunomodulation. These results demonstrate that adenosine receptor ligands are potential candidates for the treatment of type 1 diabetes.—Nemeth Z. H., Bleich, D., Csóka B., Pacher P., Mabley, J. G., Himer, L., Vizi, E. S., Deitch E. A., Szabo C., Cronstein, B. N., Haskó G. Adenosine receptor activation ameliorates type 1 diabetes. FASEB J. 21, 2379–2388 (2007)