Adenosine receptor activation ameliorates type 1 diabetes

D. Bleich, B. Csóka, Z.H. Nemeth, P. Pacher, Jon Mabley, L. Himer, E.S. Vizi, E.A. Deitch, C. Szabo, B.N. Cronstein, G. Hasko

Research output: Contribution to journalArticleResearchpeer-review

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.
Original languageEnglish
Pages (from-to)2379-2388
Number of pages10
JournalFaseb journal
Volume21
Issue number10
Publication statusPublished - 31 Aug 2007

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Adenosine-5'-(N-ethylcarboxamide)
Purinergic P1 Receptors
Type 1 Diabetes Mellitus
Inbred NOD Mouse
Streptozocin
Cyclophosphamide
Purinergic P1 Receptor Agonists
Cytokines
Chemokine CCL3
Immunomodulation
Interleukin-12
Helper-Inducer T-Lymphocytes
Endotoxins
Adenosine
Autoimmune Diseases
Pancreas
Cell Death
Therapeutics
Tumor Necrosis Factor-alpha
Ligands

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Bleich, D., Csóka, B., Nemeth, Z. H., Pacher, P., Mabley, J., Himer, L., ... Hasko, G. (2007). Adenosine receptor activation ameliorates type 1 diabetes. Faseb journal, 21(10), 2379-2388.
Bleich, D. ; Csóka, B. ; Nemeth, Z.H. ; Pacher, P. ; Mabley, Jon ; Himer, L. ; Vizi, E.S. ; Deitch, E.A. ; Szabo, C. ; Cronstein, B.N. ; Hasko, G. / Adenosine receptor activation ameliorates type 1 diabetes. In: Faseb journal. 2007 ; Vol. 21, No. 10. pp. 2379-2388.
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Bleich, D, Csóka, B, Nemeth, ZH, Pacher, P, Mabley, J, Himer, L, Vizi, ES, Deitch, EA, Szabo, C, Cronstein, BN & Hasko, G 2007, 'Adenosine receptor activation ameliorates type 1 diabetes', Faseb journal, vol. 21, no. 10, pp. 2379-2388.

Adenosine receptor activation ameliorates type 1 diabetes. / Bleich, D.; Csóka, B.; Nemeth, Z.H.; Pacher, P.; Mabley, Jon; Himer, L.; Vizi, E.S.; Deitch, E.A.; Szabo, C.; Cronstein, B.N.; Hasko, G.

In: Faseb journal, Vol. 21, No. 10, 31.08.2007, p. 2379-2388.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Bleich, D.

AU - Csóka, B.

AU - Nemeth, Z.H.

AU - Pacher, P.

AU - Mabley, Jon

AU - Himer, L.

AU - Vizi, E.S.

AU - Deitch, E.A.

AU - Szabo, C.

AU - Cronstein, B.N.

AU - Hasko, G.

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N2 - 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.

AB - 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.

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Bleich D, Csóka B, Nemeth ZH, Pacher P, Mabley J, Himer L et al. Adenosine receptor activation ameliorates type 1 diabetes. Faseb journal. 2007 Aug 31;21(10):2379-2388.