TNF-α upregulates adenosine 2b (A2b) receptor expression and signaling in intestinal epithelial cells: a basis for A2bR overexpression in colitis

Kolachala, Vasantha L.; Asamoah, Vivian; Wang, L.; Obertone, Tracy S.; Ziegler, Thomas R.; Merlin, Didier; Sitaraman, S

doi:10.1007/s00018-005-5328-4

Cited by 102 publications

(125 citation statements)

References 37 publications

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“…All mice that were fed 3% DSS for 7 days developed signs of severe colitis (clinical score: 9.4 Ϯ 1.0; histological score: 9.1 Ϯ 2.3), presented as bloody diarrhea and weight loss. Consistent with our previous observations (9), A 2B AR mRNA levels increased 2.3 Ϯ 0.3-fold (*p Ͻ 0.05), compared with control mice that received water (Fig. 5A).…”

Section: Tnf-␣ Does Notsupporting

confidence: 92%

“…In our previous studies, we observed the up-regulation of A 2B AR by TNF-␣ in colonic epithelial cells and in the DSS mouse model of colitis (9). Using a pFLR7 promoter-reporter construct that contained either the 1.4-kb and 2.5-kb fragments of the A 2B AR promoter, we found that TNF-␣ did not increase A 2B AR promoter activity (Fig.…”

Section: Discussionmentioning

confidence: 69%

“…1, the relative luciferase activity in pFRL7 1.4 A 2B AR total lysates (11.6 Ϯ 1.3) was ϳ10 times greater than that in empty vector transfectants (1.9 Ϯ 0.13). TNF-␣, however, did not increase A 2B AR promoter activity (11.01 Ϯ 0.3), despite the increase in A 2B AR mRNA levels (9). Also, TNF-␣ had no effect on luciferase activity from a longer 2.5-kb fragment of the A 2B AR promoter.…”

Section: Tnf-␣ Does Notmentioning

confidence: 87%

“…We have observed that A 2B AR mRNA and protein expression are up-regulated in human and animal models of inflammatory bowel disease (9). We have demonstrated that deletion of the A 2B AR gene protects against murine colitis (10).…”

mentioning

confidence: 91%

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Adenosine 2B Receptor Expression Is Post-transcriptionally Regulated by MicroRNA

Kolachala

Wang

Obertone

et al. 2010

Journal of Biological Chemistry

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We have reported that epithelial adenosine 2B receptor (A 2B AR) mRNA and protein are up-regulated in colitis, which we demonstrated to be regulated by tumor necrosis factor ␣ (TNF-␣). Here, we examined the mechanism that governs A 2B AR expression during colitis. A 1.4-kb sequence of the A 2B AR promoter was cloned into the pFRL7 luciferase vector. Anti-microRNA (miRNA) was custom-synthesized based on specific miRNA binding sites. The binding of miRNA to the 3-untranslated region (UTR) of A 2B AR mRNA was examined by cloning this 3-UTR downstream of the luciferase gene in pMIR-REPORT. In T84 cells, TNF-␣ induced a 35-fold increase in A 2B AR mRNA but did not increase promoter activity in luciferase assays. By nuclear run-on assay, no increase in A 2B AR mRNA following TNF-␣ treatment was observed. Four putative miRNA target sites (miR27a, miR27b, miR128a, miR128b) in the 3-UTR of the A 2B AR mRNA were identified in T84 cells and mouse colon. Pretreatment of cells with TNF-␣ reduced the levels of miR27b and miR128a by 60%. Over expression of premiR27b and pre-miR128a reduced A 2B AR levels by >60%. Blockade of miR27b increased A 2B AR mRNA levels by 6-fold in vitro. miR27b levels declined significantly in colitis-affected tissue in mice in the presence of increased A 2B AR mRNA. Collectively, these data demonstrate that TNF-␣-induced A 2B AR expression in colonic epithelial cells is post-transcriptionally regulated by miR27b and miR128a and show that miR27b influences A 2B AR expression in murine colitis.

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Section: Tnf-␣ Does Notsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 69%

Section: Tnf-␣ Does Notmentioning

confidence: 87%

mentioning

confidence: 91%

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Adenosine 2B Receptor Expression Is Post-transcriptionally Regulated by MicroRNA

Kolachala

Wang

Obertone

et al. 2010

Journal of Biological Chemistry

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“…The A2B adenosine receptor differs from the other adenosine receptors by its relative low affinity for adenosine (Feoktistov and Biaggioni, 1997). A2B is transcriptionally induced by hypoxia-inducible factor-1a activation (Eltzschig et al, 2003;Feoktistov et al, 2004), TNF-a, IL-1b, IFN-g and extracellular adenosine (Xaus et al, 1999;Kolachala et al, 2005;St Hilaire et al, 2008).…”

Section: Adenosine Receptorsmentioning

confidence: 99%

Extracellular adenosine triphosphate and adenosine in cancer

2010

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Adenosine triphosphate (ATP) is actively released in the extracellular environment in response to tissue damage and cellular stress. Through the activation of P2X and P2Y receptors, extracellular ATP enhances tissue repair, promotes the recruitment of immune phagocytes and dendritic cells, and acts as a co-activator of NLR family, pyrin domain-containing 3 (NLRP3) inflammasomes. The conversion of extracellular ATP to adenosine, in contrast, essentially through the enzymatic activity of the ecto-nucleotidases CD39 and CD73, acts as a negativefeedback mechanism to prevent excessive immune responses. Here we review the effects of extracellular ATP and adenosine on tumorigenesis. First, we summarize the functions of extracellular ATP and adenosine in the context of tumor immunity. Second, we present an overview of the immunosuppressive and pro-angiogenic effects of extracellular adenosine. Third, we present experimental evidence that extracellular ATP and adenosine receptors are expressed by tumor cells and enhance tumor growth. Finally, we discuss recent studies, including our own work, which suggest that therapeutic approaches that promote ATP-mediated activation of inflammasomes, or inhibit the accumulation of tumorderived extracellular adenosine, may constitute effective new means to induce anticancer activity.

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

Antonioli

Fornai

Colucci

et al. 2008

Inflammatory Bowel Diseases

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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.

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TNF-α upregulates adenosine 2b (A2b) receptor expression and signaling in intestinal epithelial cells: a basis for A2bR overexpression in colitis

Cited by 102 publications

References 37 publications

Adenosine 2B Receptor Expression Is Post-transcriptionally Regulated by MicroRNA

Adenosine 2B Receptor Expression Is Post-transcriptionally Regulated by MicroRNA

Extracellular adenosine triphosphate and adenosine in cancer

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

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