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Adenosine receptor activation ameliorates type 1 diabetes

Zoltán H. Németh^*, David Bleich, Balázs Csóka^*, Pál Pacher, Jon G. Mabley, Leonóra Himer^||, E. Sylvester Vizi^||, Edwin A. Deitch^*, Csaba Szabó^*, Bruce N. Cronstein^¶ and György Haskó^*,||,1

^* Department of Surgery and

Department of Medicine, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, New Jersey, USA;

Section on Oxidative Stress and Tissue Injury, Laboratory of Physiological Studies, National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland, USA;

School of Pharmacy and Biomolecular Sciences, University of Brighton, Cockcroft Building, Brighton, UK;

^|| Department of Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Hungary; and

^¶ Division of Clinical Pharmacology, Department of Medicine, New York University School of Medicine, New York, New York, USA

¹Correspondence: Department of Surgery, UMDNJ-New Jersey Medical School, 185 South Orange Ave., University Heights, Newark, NJ 07103, USA. E-mail: haskoge{at}umdnj.edu

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 multiple-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 A₁ receptor agonist 2-chloro-N⁶-cyclopentyladenosine (CCPA) and A₃ receptor agonist N⁶-(3-iodobenzyl)-adenosine-5'-N-methyluronamide (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 ß-cell death in vitro, but NECA strongly suppressed expression of the proinflammatory cytokines TNF-, MIP-1, IL-12, and IFN- 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.—Németh, Z. H., Bleich, D., Csóka, B., Pacher, P., Mabley, J. G., Himer, L., Vizi, E. S., Deitch, E. A., Szabó, C., Cronstein, B. N., Haskó, G. Adenosine receptor activation ameliorates type 1 diabetes.

Key Words: immune • islet • inflammation

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