title: 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 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 A2B 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 A2A receptor KO mice and the selective A2A 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 A2A receptors. NECA failed to prevent cytokine-induced beta-cell death in vitro, but NECA strongly suppressed expression of the proinflammatory cytokines TNF-alpha, MIP-1alpha, IL-12, and IFN-gamma 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.
authors.affiliation: Department of Surgery, UMDNJ-New Jersey Medical School, 185 South Orange Ave., University Heights, Newark, NJ 07103, USA.
authors.forename: Zoltán H
authors.initials: ZH
authors.lastname: Németh
authors.forename: David
authors.initials: D
authors.lastname: Bleich
authors.forename: Balázs
authors.initials: B
authors.lastname: Csóka
authors.forename: Pál
authors.initials: P
authors.lastname: Pacher
authors.forename: Jon G
authors.initials: JG
authors.lastname: Mabley
authors.forename: Leonóra
authors.initials: L
authors.lastname: Himer
authors.forename: E Sylvester
authors.initials: ES
authors.lastname: Vizi
authors.forename: Edwin A
authors.initials: EA
authors.lastname: Deitch
authors.forename: Csaba
authors.initials: C
authors.lastname: Szabó
authors.forename: Bruce N
authors.initials: BN
authors.lastname: Cronstein
authors.forename: György
authors.initials: G
authors.lastname: Haskó
mesh_terms: D019830:Adenosine-5'-(N-ethylcarboxamide) / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D002478:Cells, Cultured / Q000187:drug effects / Q000502:physiology; D016207:Cytokines / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology / Q000517:prevention & control; D003922:Diabetes Mellitus, Type 1 / Q000473:pathology / Q000503:physiopathology* / Q000517:prevention & control*; D005784:Gene Amplification; D007328:Insulin / Q000378:metabolism; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D058906:Purinergic P1 Receptor Agonists; D018047:Receptors, Purinergic P1 / Q000235:genetics / Q000502:physiology*; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology
chemical_list: D016207:Cytokines; D007328:Insulin; D058906:Purinergic P1 Receptor Agonists; D018047:Receptors, Purinergic P1; D019830:Adenosine-5'-(N-ethylcarboxamide)