Pharmacological modulation of adenosine system: Novel options for treatment of inflammatory bowel diseases

Abstract

Inflammatory bowel diseases (IBDs) are chronic disorders resulting from abnormal and persistent immune responses which lead to severe tissue injury and disturbances in digestive motor/secretory functions. At present, pharmacotherapy represents the cornerstone for the management of IBDs, and recent advances in understanding the immunopathogenesis of intestinal inflammation suggest the adenosine system as an attractive target for development of novel drugs against gut inflammatory disorders. Consistent evidence indicates that adenosine plays a relevant role in the regulation of immune system via interaction with specific cell-membrane G-protein-coupled receptors (A(1), A(2a), A(2b), and A(3)). Moreover, this nucleoside is implicated in the control of enteric neurotransmission and gut motor functions. In the presence of inflammation, the adenosine system acts as a sensible sensor apparatus, which, through dynamic modifications in the expression of ecto-enzymes and purinergic receptors, adapts its metabolism to tissue health status and contributes to the mechanisms deputed to the protection of tissues against inflammatory injuries. In keeping with these concepts, it is becoming increasingly appreciated that drugs targeted on adenosine receptors or enzymes responsible for adenosine catabolism can exert beneficial effects on experimental models of intestinal inflammation. This review aims to discuss the role of adenosine in the regulation of enteric immune responses and gut neuromuscular functions in the presence of inflammation, as well as to highlight the mechanisms through which the pharmacological modulation of adenosine pathways may have potential applications for the therapeutic management of IBDs.

Purinergic receptors and gastrointestinal secretomotor function

“…This illustrates a new important benefit of A 3 receptor agonists in preventing abnormalities in purine gene expression in colitis. A review by Antonioli et al [2] discusses the pharmacological modulation of adenosinergic pathways in the therapeutic management of IBD. Adenosine A 1 , A 2a , A 2b , and A 3 receptors are potential therapeutic targets as regulators of gut enteric immune responses and all components of gut motor reflexes [2,27].…”

“…In addition, we review recent findings on purinergic regulation of gastric secretions, and in relation to gastric mucosal protection. Our review would not be complete without a very brief description of the emerging role of purinergic receptors as therapeutic targets in IBD [2] or implications of purine receptor abnormalities (up-or downregulation) in GI diarrhea diseases. The reader is also referred to more general reviews on purinergic signaling [12], GI secretomotor function and dysfunction [25,26], epithelial secretion, and hepatobiliary function [92].…”

Adenosine as an endogenous immunoregulator in cancer pathogenesis: where to go?

“…However, this action of adenosine on immune system is determined by its bioavailability and adenosine receptor expression on the immune cells, which are present within tumor microenvironment. Under normal conditions, adenosine is mainly generated at the intracellular level from S-adenosylhomocysteine by Sadenosylhomocysteine hydrolase and transported across cell membranes via purine transporters [29]. Level of adenosine in extracellular environment is controlled by nucleoside or purine transporters [30,31].…”

“…In addition to this, T cell-specific deletion of HIF-1α in mice prevented them from acquiring sepsis and led to exaggerated proinflammatory immune response required to clear bacteria efficiently from circulation and increased their survival; these elevated HIF-1α levels may lead to immunosuppression [243]. CD73 (ecto-5′-nucleotidase) and CD39 [nucleoside triphosphate dephosphorylase (NTPD)] play major roles in maintaining high extracellular concentration of adenosine during metabolic stress (i.e., tumor) by directly catabolizing ATP into adenosine [29]. However, adenosine bioavailability is also influenced by an enzyme known as adenosine deaminase (ADA).…”

Activation of adenosine low-affinity A3 receptors inhibits the enteric short interplexus neural circuit triggered by histamine

“…In human EC cells or ENS, functional A3 receptors can be revealed by selective A3 agonists [i.e., It has been hypothesized that high-affinity inhibitory A1 receptors are involved in physiological regulation whereas low-affinity inhibitory A3 receptors are more likely to be activated by eADO in pathophysiological states because they require high levels of eADO to activate them that are more easily achieved in disease states (3,40,44,48,57,58). Ongoing studies are beginning to unravel the potential protective and therapeutic role of selectively targeting eADO (26, 53), A3 (37, 43), A2A (2,8,45,46), and A2B receptors (41) in inflamed gut and models of inflammatory bowel diseases (IBD) with drug agonists or antagonists depending on the receptor. Endogenous adenosine is a metabolite of ATP that acts at A1, A2A, and A2B receptors to influence mucosal secretion and motor reflexes (18).…”