The Adenosine A2b Receptor: Its Role in Inflammation

Ham, Jack; Rees, Dafydd Aled

doi:10.2174/187153008786848303

Cited by 46 publications

(33 citation statements)

References 149 publications

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“…Mediation through the A2a receptor has been reported to be beneficial in wound healing, inflammatory bowel disease, ischaemia, arthritis and chronic obstructive pulmonary disease. A2b receptor actions are generally thought to be proinflammatory although anti-inflammatory properties have also been reported [53][54][55].…”

Section: Discussionmentioning

confidence: 99%

“…In this study, we have not attempted to identify the specific adenosine receptor(s) involved although previous studies indicate that the A2b subtype is highly expressed in FS cells [15,16]. The A2b receptor has been shown to play a significant role in inflammatory processes [55]. Whole animal experiments will, however, be needed to understand the precise role of adenosine signalling in the control of inflammation.…”

Section: Discussionmentioning

confidence: 99%

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Adenosine regulates thrombomodulin and endothelial protein C receptor expression in folliculostellate cells of the pituitary gland

Rees

Giles

Lewis

et al. 2009

Purinergic Signalling

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Adenosine stimulates the release of interleukin 6 (IL-6) and vascular endothelial growth factor from folliculostellate cells of the anterior pituitary gland indicating that such cells are also involved in the communication between the immune and endocrine systems during stress and inflammation. In order to understand the precise actions of adenosine on folliculostellate cells, DNA microarray analysis was used to determine global changes in gene expression. Hierarchical clusters revealed, of the genes that had altered expression, the majority were suppressed and many, such as B cell translocation gene 2 and cyclindependent kinase inhibitor 2b were related to cell cycle arrest or inhibition of proliferation. Several of the upregulated genes were associated with cytokine signalling or membrane receptor activity. The most notable of these being IL-6, sulfiredoxin 1, endothelial protein C receptor (EPCR) and thrombomodulin (THBD) which can all play a role in controlling inflammation. The EPCR and THBD pathway is well known in anti-coagulation but also has anti-inflammatory and anti-apoptotic properties. Upregulation of EPCR and THBD in folliculostellate cells was confirmed by qRT-PCR and western blotting analysis and their expression were also demonstrated in many of the hormone-secreting cells of the anterior pituitary gland. Our findings suggest that adenosine can stimulate expression of stress and inflammation related genes from folliculostellate cells of the anterior pituitary gland. These genes include EPCR and THBD, neither of which has been previously identified in the pituitary gland.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Adenosine regulates thrombomodulin and endothelial protein C receptor expression in folliculostellate cells of the pituitary gland

Rees

Giles

Lewis

et al. 2009

Purinergic Signalling

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“…The adenosine receptors on F-S cells signal via Gq/PLC (A 1 R, A 2B R) and Gs/adenyl cyclase (A 2B R), the stimulation of A 2B receptors causing proliferation of TtT/GF cells and increasing VEGF and IL-6 production [88,89] and thrombomodulin expression and gap junction proteins [78]. The source of adenosine is unclear; it is derived from the diet, but may be generated locally because ecto-5'-nucleotidase is expressed by ~20% of pituitary cells, in particular lactotrophs and somatotrophs, and coculture of TtT/GF cells with somatomammotrophs increases the expression of connexon 43 [88].…”

Section: Inputs To F-s Cells: Receptors and Mecha-nisms Of Actionmentioning

confidence: 99%

Folliculo-stellate Cells: Paracrine Communicators in the Anterior Pituitary

Morris¹

2011

TONEUROEJ

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Most research on the anterior pituitary (adenohypophysis) has concentrated on the endocrine cells characterized by their complement of cytoplasmic dense-cored vesicles containing the classic anterior pituitary hormones. However it has become increasingly clear over the last 20 years that cells first identified more than 50 years ago in the basis that they lack such dense-cored vesicles and now known generically as folliculo-stellate or follicular cells have important physiological functions and act as an adenohypophysis wide communication system. This brief review reveals the need for this communication system, what we know of the plethora of products secreted by Folliculo-Stellate cells, the many receptors to which they respond, and in particular, the role of these enigmatic cells in the physiology of the stress/immune axis, the gonadotroph cells and the pituitary vasculature. Finally we review the current evidence that cells in this category can act as stem cells in the adult pituitary.

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“…Until recently, the A 2B AR was presumed to have minor physiologic significance, in part due to its relatively low affinity for the endogenous agonist adenosine (Feoktistov and Biaggioni, 1997;Fredholm et al, 2001b). However the substantial increase in extracellular adenosine concentration (Sommerschild and Kirkebøen, 2000) and the upregulation of A 2B AR expression under pathologic conditions such as hypoxia (Kong et al, 2006) and inflammation (Ham and Rees, 2008) suggest a possible maladaptive role of the A 2B AR. Consequently, A 2B AR antagonists are currently being explored as a novel therapeutic strategy for the treatment of inflammation (Ham and Rees, 2008), asthma and chronic obstructive pulmonary disease (Polosa and Blackburn, 2009), and diabetic nephropathy (Cárdenas et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Ligand-Independent Adenosine A2B Receptor Constitutive Activity as a Promoter of Prostate Cancer Cell Proliferation

Vecchio

Tan

Gregory

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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Aberrant ligand-independent G protein-coupled receptor constitutive activity has been implicated in the pathophysiology of a number of cancers. The adenosine A 2B receptor (A 2B AR) is dynamically upregulated under pathologic conditions associated with a hypoxic microenvironment, including solid tumors. This, in turn, may amplify ligand-independent A 2B AR signal transduction. The contribution of A 2B AR constitutive activity to disease progression is currently unknown yet of fundamental importance, as the preferred therapeutic modality for drugs designed to reduce A 2B AR constitutive activity would be inverse agonism as opposed to neutral antagonism. The current study investigated A 2B AR constitutive activity in a heterologous expression system and a native 22Rv1 human prostate cancer cell line exposed to hypoxic conditions (2% O 2 ). (4-chlorophenyl)piperazide-1-sulfonyl)phenyl)-1-propylxanthine), mediated a concentration-dependent decrease in baseline cAMP levels in both cellular systems. Proliferation of multiple prostate cancer cell lines was also attenuated in the presence of PSB-603. Importantly, both the decrease in baseline cAMP accumulation and the reduction of proliferation were not influenced by the addition of adenosine deaminase, demonstrating that these effects are not dependent on stimulation of A 2B ARs by the endogenous agonist adenosine. Our study is the first to reveal that wild-type human A 2B ARs have high constitutive activity in both model and native cells. Furthermore, our findings demonstrate that this ligand-independent A 2B AR constitutive activity is sufficient to promote prostate cancer cell proliferation in vitro. More broadly, A 2B AR constitutive activity may have wider, currently unappreciated implications in pathologic conditions associated with a hypoxic microenvironment.

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The Adenosine A2b Receptor: Its Role in Inflammation

Cited by 46 publications

References 149 publications

Adenosine regulates thrombomodulin and endothelial protein C receptor expression in folliculostellate cells of the pituitary gland

Adenosine regulates thrombomodulin and endothelial protein C receptor expression in folliculostellate cells of the pituitary gland

Folliculo-stellate Cells: Paracrine Communicators in the Anterior Pituitary

Ligand-Independent Adenosine A2B Receptor Constitutive Activity as a Promoter of Prostate Cancer Cell Proliferation

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