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.

The novel inosine analogue, INO-2002, protects against diabetes development in multiple low-dose streptozotocin and non-obese diabetic mouse models of type I diabetes

“…This protection was associated with decreased pancreatic levels of Th1 cytokines, IL-12, TNF-a and IFN-g, and the chemokine MIP-1a (Nemeth et al 2007). Interestingly, using both specific receptor antagonists and transgenic knockout mice, the protection by adenosine against type I diabetes was found to be mediated through activation of the A 2b receptor subtype rather than the A 2a (Nemeth et al 2007), implicating both A 2a and A 2b receptor subtypes in adenosines modulation of the inflammatory system. The results obtained using adenosine and its receptor agonists in models of type I diabetes mimic those observed with both inosine and INO-2002, suggesting a role for A 2b receptor activation in inosine/INO-2002-mediated protection.…”

“…Activation of the adenosine A 2a receptor downregulates inflammation and protect against tissue damage (Ohta & Sitkovsky 2001) and inosine's inhibitory effect on inflammatory cytokine production is mediated in part by activation of this adenosine receptor (Hasko et al 2000). Recently, we have demonstrated that adenosine receptor activation ameliorates type I diabetes, as adenosine-5 0 -N-ethylcarboxanide (NECA), a non-selective adenosine receptor agonist, protects against MLDS-and cyclophosphamide-induced diabetes in NOD mice (Nemeth et al 2007). This protection was associated with decreased pancreatic levels of Th1 cytokines, IL-12, TNF-a and IFN-g, and the chemokine MIP-1a (Nemeth et al 2007).…”

“…Recently, we have demonstrated that adenosine receptor activation ameliorates type I diabetes, as adenosine-5 0 -N-ethylcarboxanide (NECA), a non-selective adenosine receptor agonist, protects against MLDS-and cyclophosphamide-induced diabetes in NOD mice (Nemeth et al 2007). This protection was associated with decreased pancreatic levels of Th1 cytokines, IL-12, TNF-a and IFN-g, and the chemokine MIP-1a (Nemeth et al 2007). Interestingly, using both specific receptor antagonists and transgenic knockout mice, the protection by adenosine against type I diabetes was found to be mediated through activation of the A 2b receptor subtype rather than the A 2a (Nemeth et al 2007), implicating both A 2a and A 2b receptor subtypes in adenosines modulation of the inflammatory system.…”

High Levels of Adenosine Deaminase on Dendritic Cells Promote Autoreactive T Cell Activation and Diabetes in Nonobese Diabetic Mice

“…Other reports indicated that CD39, the ectoenzyme mediating the conversion from ATP to adenosine on the cell surface, may be used by Tregs to regulate adenosine levels and, thus, exert their suppressive effects on other T cells (4,5). With respect to T1D, Haskó's group (29) reported several years ago that in drug-induced T1D (in CD-1 mice), A2BR signaling inhibited diabetogenesis. That report established a role for adenosine signaling in T1D and set the groundwork for our work.…”

Rutin restores adenosine deaminase activity in serum and the liver and improves biochemical parameters in streptozotocin-induced diabetic rats

“…Adenosine is a potent endogenous antiinflammatory and immunosuppressive molecule that is released from cells into the extracellular space at sites of inflammation and tissue injury (Németh et al, 2007). One key enzyme that has an important biological role in the metabolism of purine nucleosides is Adenosine deaminase (ADA), which catalyzes irreversible hydrolytic deamination of adenosine into inosine (Uz et al, 2005).…”