Adenosine: An immune modulator of inflammatory bowel diseases

Abstract

Inflammatory bowel disease (IBD) is a common and lifelong disabling gastrointestinal disease. Emerging treatments are being developed to target inflammatory cytokines which initiate and perpetuate the immune response. Adenosine is an important modulator of inflammation and its anti-inflammatory effects have been well established in humans as well as in animal models. High extracellular adenosine suppresses and resolves chronic inflammation in IBD models. High extracellular adenosine levels could be achieved by enhanced adenosine absorption and increased de novo synthesis. Increased adenosine concentration leads to activation of the A2a receptor on the cell surface of immune and epithelial cells that would be a potential therapeutic target for chronic intestinal inflammation.Adenosine is transported via concentrative nucleoside transporter and equilibrative nucleoside transporter transporters that are localized in apical and basolateral membranes of intestinal epithelial cells, respectively. Increased extracellular adenosine levels activate the A2a receptor, which would reduce cytokines responsible for chronic inflammation.

Role of the Transporter Regulator Protein (RS1) in the Modulation of Concentrative Nucleoside Transporters (CNTs) in Epithelia

“…Luminal adenosine exerts a variety of physiological effects in both renal and intestinal epithelia. Adenosine is a modulator of tubuloglomerular feedback (Thomson et al, 2000) and a protective agent in intestinal inflammatory disease (Ye and Rajendran, 2009). CNT proteins, particularly CNT2 and CNT3, are major candidates to remove adenosine from the extracellular space, because they are high-affinity concentrative adenosine transporters (Pastor-Anglada et al, 2008).…”

The Blockade of Adenosine Deaminase Ameliorates Chronic Experimental Colitis through the Recruitment of Adenosine A2Aand A3Receptors

“…In particular, the involvement of A 3 receptors in mediating the anti-inflammatory effects resulting from adenosine deaminase blockade seem to be appreciable for few phlogistic parameters. One explanation for this differential recruitment of receptor subtypes could be ascribed to an increase in the activity of nucleoside transporters arising from the activation of A 2A receptors (Pinto-Duarte et al, 2005;Ye and Rajendran, 2009). In this regard, the greater stimulation of A 2A receptors by the pharmacological blockade of adenosine deaminase could be related to an increased activity of nucleoside transporters to avoid a spread of extracellular adenosine, sufficient to activate A 3 receptors and the low-affinity A 2B receptor.…”

Purinergic signalling in the gastrointestinal tract and related organs in health and disease

“…ATP released from colonic mucosal epithelial cells of IBS patients excites enteric cholinergic motor neurons via P2X receptors [29]. The role of adenosine as an immune modulator of IBD has been reviewed [736]. Genetic polymorphisms of CD39 have been linked to Crohn's disease [413].…”