Adenosine and Adenosine Receptors in Rheumatoid Arthritis

Melissa Padovan; Fabrizio Vincenzi; Marcello Govoni; Alessandra Bortoluzzi; Pier Andrea Borea; Katia Varani


Int J Clin Rheumatol. 2013;8(1):13-25. 

In This Article

Adenosine & Adenosine Receptors

Adenosine is a purine nucleoside identified as an endogenous and ubiquitous molecule regulator of different tissues and cell functions.[28] Adenosine is generated in the extracellular space by the breakdown of ATP through a series of ectoenzymes, including apyrase and ecto-5'-nucleotidase.[29] Adenosine is phosphorylated to AMP by adenosine kinase or degraded to inosine by adenosine deaminase.[30] Adenosine production from the hydrolysis of AMP is mediated by a cytosolic 5'-nucleotidase or by the hydrolysis of S-adenosylhomocysteine.[30] The levels of adenosine in the interstitial fluids are in the range of 20–200 nM but they dramatically increase under metabolically unfavorable conditions.[31] Adenosine effects are widespread and mediated by the interaction with different adenosine receptor (AR) subtypes, which are able to modulate cell signaling transduction (Table 1).[32] ARs are characterized by seven transmembrane domains with the N- and C-terminus in the extracellular side, and the presence of intracellular and extracellular loops.[33] A1AR stimulation through the interaction with Gi/Go proteins modulates different cellular effectors as adenylate cyclase (AC) and phospholypase C (PLC).[34] The A2A and A2BARs through coupling with Gs proteins activate AC and increase cyclic AMP levels.[31] A3ARs, via the interaction with Gi inhibit adenylate cyclase decreasing cyclic AMP accumulation and protein kinase A (PKA) activity. In addition, A3ARs via coupling with Gq proteins stimulate PLC, causing an increase of calcium levels from intracellular stores, and modulate the protein kinase C (PKC) activity (Figure 1).[35,36]

Figure 1.

Principal signaling pathways activated by adenosine receptors.
AC: Adenylate cyclase; AR: Adenosine receptor; cAMP: Cyclic adenosine monophosphate; cAMP-GEF1: cAMP-regulated guanine nucleotide exchange factor 1; CDC42: Cell division control protein 42; DAG: Diacylglycerol; Elk-1: E-26-like transcription factor-1; ERK: Extracellular signal-regulated kinase; Gαq/11: G-protein q/11 α-subunit; Gβ: G-protein β-subunit; Gγ: G-protein γ-subunit; Giα: Inhibitory G-protein symbol-subunit; Gsα: Stimulatory G-protein α-subunit; GSK3β: Glycogen synthase kinase 3β; IKK: Inhibitor of NF-κB (IkB) kinase; IP3: Inositol 1,4,5-trisphosphate; MAPK: Mitogen-activated protein kinase; MEK: Mitogen-activated protein kinase kinase; NF-κB: Nuclear factor-κB; PDZ-GEF1: PDZ domain-containing guanine nucleotide exchange factor 1; PI3K: Phosphoinositide 3-kinase; PIP2: Phosphatidylinositol 4,5-bisphosphate; PKA: Protein kinase A; PLC-β: Phospholipase C-β; STAT3: Signal transducer and activator of transcription 3.

The widespread distribution in different cells and tissues of the ARs could suggest their potential involvement in various pathologies and the possible use as selective pharmacological targets.

A1 Adenosine Receptors

A1ARs are widely distributed not only in the CNS, but also in peripheral tissues.[37] Adenosine, by A1AR activation, produces inhibition of neurotransmitter release and induces neuronal hyperpolarization mediating sedative, anticonvulsant, anxiolitic and locomotor depressant effects.[38] Literature evidence has indicated the involvement of A1ARs in controlling pain transmission, producing antinociceptive effects in various animal models.[39–42] In the cardiovascular system, A1ARs mediate negative chronotropic, dromotropic and ionotropic effects, suggesting the potential use of A1AR agonists as cardioprotective agents and in the treatment of arrhythmias and atrial fibrillation.[43] In the kidney, A1ARs mediate vasoconstriction, decrease glomerular filtration rate, inhibit renin secretion and their inhibition could represent a novel strategy for the treatment of hypertension and edema.[44] The role of adenosine in regulating the respiratory system is well known and elevated levels of adenosine have been found in bronchoalveolar lavage (BAL), blood and exhaled breath condensate of patients with asthma and chronic obstructive pulmonary disease (COPD). A1AR antagonists could also be used in asthma and in COPD since adenosine induces acute bronchoconstriction via stimulation of A1ARs.[45,46]

A2A Adenosine Receptors

It is well known that A2AARs are found ubiquitously in the body, and their expression is highest in the immune system and the striatopallidal system in the brain.[47,48] Several studies have suggested the possible involvement of A2AARs in the pathogenesis of neuronal disorders, including Huntington's disease and Parkinson's disease. In particular, an aberrant increase of A2AAR density in peripheral blood cells of Huntington's disease and Parkinson's disease patients in comparison with age-matched healthy subjects has been demonstrated.[49,50] Accordingly, A2A antagonists currently constitute an attractive nondopaminergic option for use in the treatment of Parkinson's disease.[51] Adenosine has important protective effects on the cardiovascular system. Activation of the A2AAR subtype on coronary smooth muscle cells, endothelial cells and monocytes/macrophages results in vasodilation, neo-angiogenesis and inhibition of proinflammatory cytokine production.[52,53] An upregulation of A2AAR was found in peripheral circulating cells of end-stage chronic heart failure patients.[54] Literature evidence reports an important role of A2AARs in chronic airway diseases, as suggested by the genetic removal of A2AAR that leads to enhanced pulmonary inflammation, mucus production and alveolar airway destruction.[55]

A2B Adenosine Receptors

A2BAR is expressed in the brain, spleen, lung, colon, heart and kidney, where it is primarily localized to the vasculature.[56] A2BAR expression has been detected in vascular endothelium and smooth muscle cells where it has been implicated in the regulation of vascular tone through receptor-mediated vasodilatory effects.[57] Activation of A2BARs prevent cardiac remodeling after myocardial infarction and exert protective effects from infarction in ischemic postconditioning.[58] Degranulation of mast cells and subsequent mediator release is an important component of the bronchoconstriction observed in asthma.[59,60] Importantly, investigation of ARs on mast cells implicate A2BAR signaling in degranulation and mediator release.[61] Identification of A2BAR signaling as a potential pathway in the pathogenesis of asthma prompted its investigation in other chronic conditions affecting the lung, including COPD and idiopathic pulmonary fibrosis.[62] A protective role for A2BAR antagonists has been proposed in the resolution of pulmonary inflammation and fibrotic processes.[63,64] In addition, it has been observed that A2BARs are downregulated in COPD patients probably due to oxidative/nitrosative stress.[65] It has also been reported that A2BARs in intestinal epithelial cells mediated Cl secretion through an increase in cyclic AMP levels.[31]

A3 Adenosine Receptors

The tissue distribution of A3ARs has been well investigated and suggests that these receptors are primarily expressed in lung, liver and immune cells. A minor expression of A3ARs is reported in kidney, heart, brain and gastrointestinal tissues.[36] It has been reported that A3ARs activation in the brain may contribute to neurotransmission..[66] A proconvulsant effect of A3ARs has been observed in the immature brain, suggesting the possibility of facilitating seizure-induced neuronal damage.[67] A nociceptive role for A3ARs involving both CNS and proinflammatory effects in peripheral tissues has been highlighted.[68] Moreover, prolonged A3AR stimulation is able to transform the effects from protective to injurious, increasing the excitotoxicity.[69] Glial A3AR activation by high adenosine levels, caused by a brain injury, may be implicated in neuroinflammatory tissue responses.[70] There is also evidence that A3ARs enhance cellular antioxidant capacity that contribute to vasoprotection and reduce cardiac myocyte death, suggesting a strong support for an A3-dependent cardioprotective response including the reduction in infarct size, inhibition of apoptosis and improvements in postischemic contractile function.[71] Moreover A3ARs stimulate vascular growth acting with A2BARs to promote angiogenesis via the expression of angiogenic factors in mast cells or stimulate HIF-1α and VEGF expression.[72] Transcript levels of A3ARs are elevated in lung biopsies of patients with asthma or COPD where their activation mediated the inhibition of eosinophil chemotaxis.[73,74] By contrast, mice treated with selective A3 antagonists resulted in a marked attenuation of pulmonary inflammation, reduced eosinophil infiltration into the airways and decreased airway mucus production.[75]

Adenosine is present at high concentrations in cancer tissues and in the interstitial fluid of several tumors, at concentrations sufficient to interact with ARs.[31] A3ARs are present in different types of tumor cells and are involved in the tumor growth and the regulation of the cell cycle, and mediate both pro- and anti-apoptotic effects closely associated with the level of receptor activation.[76–78] A3AR density was upregulated in colon carcinoma tissues closely correlated to the disease severity. In addition, the alteration of A3ARs reflected a similar behavior shown in lymphocytes or neutrophils derived from colon cancer patients, suggesting that these receptors may represent an interesting biological marker.[79]

ARs are present in many cell types including platelets, lymphocytes, eosinophils, neutrophils, mast cells and macrophages where they mediate pro- and anti-inflammatory effects.[50,54,80] Several authors have demonstrated that human circulating blood cells (platelets, lymphocytes and neutrophils) reproduce the same receptor alterations known to be at the basis of specific diseases mainly in the cardiovascular system and CNS.[38,49,54,81,82] As a consequence, peripheral blood cells could represent a useful and easily available model to monitor receptor changes during the course of chronic rheumatic inflammatory diseases and to assess the efficacy of specific pharmacological treatments.[83–85]