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, György Haskó

Research output: Contribution to journalArticle

82 Scopus citations

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 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 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 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.

Original languageEnglish (US)
Pages (from-to)2379-2388
Number of pages10
JournalFASEB Journal
Volume21
Issue number10
DOIs
StatePublished - Aug 2007

All Science Journal Classification (ASJC) codes

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

Keywords

  • Immune
  • Inflammation
  • Islet

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  • Cite this

    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. (2007). Adenosine receptor activation ameliorates type 1 diabetes. FASEB Journal, 21(10), 2379-2388. https://doi.org/10.1096/fj.07-8213com