A2B Adenosine Receptor Gene Deletion Attenuates Murine Colitis

Kolachala, Vasantha L.; Vijay‐Kumar, Matam; Dalmasso, Guillaume; Yang, Dan; Linden, Joel; Wang, Lixin; Gewirtz, Andrew T.; Ravid, Katya; Merlin, Didier; Sitaraman, Shanthi V.

doi:10.1053/j.gastro.2008.05.049

Cited by 104 publications

(136 citation statements)

References 48 publications

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“…Recently, it has been shown indirectly by blockade of A 2B R that this receptor subtype plays a pro-inflammatory role in DSS-colitis [23]. Using the selective A 2B R agonist BAY 60-6583, our results confirm this assumption.…”

Section: Discussionsupporting

confidence: 87%

Adenosine A2A agonist and A2B antagonist mediate an inhibition of inflammation-induced contractile disturbance of a rat gastrointestinal preparation

Michael

Warstat

Michel

et al. 2009

Purinergic Signalling

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Adenosine can show anti-inflammatory as well as pro-inflammatory activities. The contribution of the specific adenosine receptor subtypes in various cells, tissues and organs is complex. In this study, we examined the effect of the adenosine A 2A receptor agonist CGS 21680 and the A 2B R antagonist PSB-1115 on acute inflammation induced experimentally by 2,4,6-trinitrobenzenesulfonic acid (TNBS) on rat ileum/jejunum preparations. Preincubation of the ileum/jejunum segments with TNBS for 30 min resulted in a concentration-dependent inhibition of acetylcholine (ACh)-induced contractions. Pharmacological activation of the A 2A R with CGS 21680 (0.1-10 µM) preincubated simultaneously with TNBS (10 mM) prevented concentration-dependently the TNBS-induced inhibition of the ACh contractions. Stimulation of A 2B R with the selective agonist BAY 60-6583 (10 µM) did neither result in an increase nor in a further decrease of ACh-induced contractions compared to the TNBS-induced inhibition. The simultaneous pre-incubation of the ileum/jejunum segments with TNBS (10 mM) and the selective A 2B R antagonist PSB-1115 (100 µM) inhibited the contractiondecreasing effect of TNBS. The effects of the A 2A R agonist and the A 2B R antagonist were in the same range as the effect induced by 1 µM methotrexate. The combination of the A 2A R agonist CGS 21680 and the A 2B R antagonist PSB-1115 at subthreshold concentrations of both agents found a significant amelioration of the TNBS-diminished contractility. Our results demonstrate that the activation of A 2A receptors or the blockade of the A 2B receptors can prevent the inflammation-induced disturbance of the AChinduced contraction in TNBS pre-treated small intestinal preparations. The combination of both may be useful for the treatment of inflammatory bowel diseases.

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Section: Discussionsupporting

confidence: 87%

Adenosine A2A agonist and A2B antagonist mediate an inhibition of inflammation-induced contractile disturbance of a rat gastrointestinal preparation

Michael

Warstat

Michel

et al. 2009

Purinergic Signalling

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“…During ischemia-reperfusion injury, signaling through A2BAR reduces the associated reperfusion injury and possesses tissueprotective potential (16,17). The coordinated induction of A2BAR during cellular hypoxia and an acute inflammatory process has to be seen as an adaptation of the affected tissues to increase vascular barrier response and to induce tissue-protective signaling through the A2BAR (18)(19)(20)(21). However, a major limitation of adenosine signaling is that once adenosine is generated into the extracellular milieu, it is also rapidly cleared through passive or active uptake.…”

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confidence: 99%

Netrin-1 Signaling Dampens Inflammatory Peritonitis

Mirakaj

Gatidou

Pötzsch

et al. 2011

The Journal of Immunology

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Previous studies implicated the anti-inflammatory potential of the adenosine 2B receptor (A2BAR). A2BAR activation is achieved through adenosine, but this is limited by its very short t1/2. To further define alternative adenosine signaling, we examined the role of netrin-1 during acute inflammatory peritonitis. In this article, we report that animals with endogenous repression of netrin-1 (Ntn1+/−) demonstrated increased cell count, increased peritoneal cytokine concentration, and pronounced histological changes compared with controls in a model of zymosan A peritonitis. Exogenous netrin-1 significantly decreased i.p. inflammatory changes. This effect was not present in animals with deletion of A2BAR (A2BAR−/−). A2BAR−/− animals demonstrated no change in cell count, i.p. cytokine concentration, or histology in response to netrin-1 injection. These data strengthen the role of netrin-1 as an immunomodulatory protein exerting its function in dependence of the A2BAR and further define alternative adenosine receptor signaling.

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“…We have demonstrated that deletion of the A 2B AR gene protects against murine colitis (10). In addition, A 2B AR antagonists mitigate colonic inflammation in murine models of colitis (11), suggesting that A 2B AR is a therapeutic target in inflammatory bowel disease and other intestinal inflammatory diseases.…”

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confidence: 91%

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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A2B Adenosine Receptor Gene Deletion Attenuates Murine Colitis

Cited by 104 publications

References 48 publications

Adenosine A2A agonist and A2B antagonist mediate an inhibition of inflammation-induced contractile disturbance of a rat gastrointestinal preparation

Adenosine A2A agonist and A2B antagonist mediate an inhibition of inflammation-induced contractile disturbance of a rat gastrointestinal preparation

Netrin-1 Signaling Dampens Inflammatory Peritonitis

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

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