Selective A2A adenosine agonist ATL-146e attenuates acute lethal liver injury in mice

Odashima, Masaru; Otaka, Michiro; Jin, Mario; Komatsu, Kyoji; Wada, Isao; Matsuhashi, Tamotsu; Horikawa, Youhei; Hatakeyama, Natsumi; Oyaké, Jinko; Ohba, Reina; Linden, Joel; Watanabe, Sumio

doi:10.1007/s00535-005-1609-9

Cited by 19 publications

(20 citation statements)

References 17 publications

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“…In liver injury, alterations in cytokine release, fatty acid metabolism, acute toxic liver injury, ischemia-reperfusion damage, and toxininduced liver fibrosis are modulated by adenosine. Adenosine effects cell changes via signaling through its four G proteincoupled receptors: A 1 , A 2a , A 2b , and A 3 (5,30,(33)(34)(35)43). Of particular relevance to the present study, adenosine regulates a number of fibrogenic functions in myofibroblastic HSC.…”

Section: Discussionmentioning

confidence: 82%

Activated hepatic stellate cells upregulate transcription of ecto-5′-nucleotidase/CD73 via specific SP1 and SMAD promoter elements

Fausther

Sheung

Saiman

et al. 2012

American Journal of Physiology-Gastrointestinal and Liver Physi

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sine is a potent modulator of liver fibrosis and inflammation. Adenosine has been shown to regulate such diverse activities as chemotaxis, contraction, and matrix production in hepatic stellate cells (HSC). Ecto-5=-nucleotidase/CD73 [EC 3.1.3.5] is the rate-limiting enzyme in adenosine production. Cd73-deficient mice are resistant to experimental liver fibrosis and have impaired adenosine generation. However, cell-specific expression and regulation of CD73 within the fibrotic liver have not been defined. In particular, prior evidence demonstrating that liver myofibroblasts, the cells believed to be responsible for matrix formation in the liver, express CD73 is lacking. Thus we tested the hypothesis that HSC and portal fibroblasts (PF), cells that undergo differentiation into liver myofibroblasts, express CD73 in a regulated fashion. We found that CD73 is weakly expressed in quiescent HSC and PF but is markedly upregulated at the transcriptional level in myofibroblastic HSC and PF. We furthermore found that CD73 protein and its functional activity are strongly increased in fibrous septa in rats subjected to experimental fibrosis. To determine the mechanism for the upregulation of Cd73 gene, we cloned the rat Cd73 promoter and then used serial truncation and site-directed mutagenesis to identify key regulatory elements. We identified two consensus SP1 motifs and one SMAD binding site, each of which was necessary for Cd73 gene upregulation. In conclusion, activated HSC upregulate Cd73 gene expression, via specific SP1 and SMAD promoter elements, after myofibroblastic differentiation. The ecto-5=-nucleotidase/CD73 enzyme is a novel cellular marker of activated liver myofibroblasts in vivo and in vitro and thus represents a promising molecular target for antifibrotic therapies in liver diseases.adenosine; hepatic fibrosis; liver myofibroblasts; portal fibroblast; purinergic signaling LIVER FIBROSIS WITH SUBSEQUENT cirrhosis is the most common cause of liver failure. This process results from an imbalance between synthesis and degradation of extracellular matrix (ECM) (25). Liver myofibroblasts are the primary cells responsible for the extensive ECM accumulation observed in liver fibrosis. These cells derive from a variety of sources including liver nonparenchymal cells, periportal and perivascular fibroblasts, and bone marrow-derived fibrocytes (37); however, the best characterized sources of liver myofibroblasts are hepatic stellate cells (HSC) and portal fibroblasts (PF) (16). As they differentiate, liver myofibroblasts become contractile, owing to production of ␣-smooth muscle actin (␣-SMA) and related proteins, and fibrogenic, owing to release of fibrillar collagens and other matrix proteins (16). Thus liver myofibroblasts represent excellent targets for antifibrotic therapies. Extracellular nucleosides (e.g., adenosine) and nucleotides (e.g., ATP) are potent signaling molecules that contribute to liver cellular homeostasis by regulating key physiological functions such as glucose metabolism, cholesterol transpor...

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Section: Discussionmentioning

confidence: 82%

Activated hepatic stellate cells upregulate transcription of ecto-5′-nucleotidase/CD73 via specific SP1 and SMAD promoter elements

Fausther

Sheung

Saiman

et al. 2012

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…as regeneration [45], injury [46,47], ischemia/reperfusion [48], and fibrosis [10]. Thus, it is scientifically worthwhile to clarify the cell-specific distribution of the various purinergic signaling components expressed in the liver tissue.…”

Section: Ecto-nucleotidasesmentioning

confidence: 99%

Expression of mediators of purinergic signaling in human liver cell lines

Goree

Lavoie

Fausther

et al. 2014

Purinergic Signalling

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Purinergic signaling regulates a diverse and biologically relevant group of processes in the liver. However, progress of research into functions regulated by purinergic signals in the liver has been hampered by the complexity of systems probed. Specifically, there are multiple liver cell subpopulations relevant to hepatic functions, and many of these have been effectively modeled in human cell lines. Furthermore, there are more than 20 genes relevant to purinergic signaling, each of which has distinct functions. Hence, we felt the need to categorize genes relevant to purinergic signaling in the best characterized human cell line models of liver cell subpopulations. Therefore, we investigated the expression of adenosine receptor, P2X receptor, P2Y receptor, and ecto-nucleotidase genes via RT-PCR in the following cell lines: LX-2, hTERT, FH11, HepG2, Huh7, H69, and MzChA-1. We believe that our findings will provide an excellent resource to investigators seeking to define functions of purinergic signals in liver physiology and liver disease pathogenesis.

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“…[29][30][31] Ohta, Sitkovsky and others showed that, among the different adenosine receptors (A1, A2A, A2B and A3), 26 the adenosine receptor 2A has a major role in the attenuation of inflammation and tissue damage. 20,21,[32][33][34][35] These studies evidenced the CD39-CD73-adenosine receptor axis blockade as a promising therapeutic target. 31,[36][37][38][39][40][41][42] In line with these studies and with the objective to better understand the mechanism involved in the acquisition by TAM of an immunoregulatory phenotype, this study aimed at evaluating the impact of ATP and ATP metabolites on TAM functions.…”

Section: Introductionmentioning

confidence: 99%

The ecto-ATPDase CD39 is involved in the acquisition of the immunoregulatory phenotype by M-CSF-macrophages and ovarian cancer tumor-associated macrophages: Regulatory role of IL-27

et al. 2016

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(2016) The ectoATPDase CD39 is involved in the acquisition of the immunoregulatory phenotype by M-CSFmacrophages and ovarian cancer tumor-associated macrophages: Regulatory role of IL-27, OncoImmunology, 5:7, e1178025, DOI: 10.1080/2162402X.2016 Targeting mediators that control the generation or the differentiation of immunoregulatory macrophages represents a therapeutic challenge to overcome tumor-associated immunosuppression. The ectonucleotidase CD39 hydrolyzes ATP into extracellular adenosine that exhibits potent immunosuppressive properties when signaling through the A2A adenosine receptor. We report here that CD14 C CD163 C TAM isolated from ovarian cancer patients and macrophages generated in vitro with M-CSF, express high levels of the membrane ectonucleotidase CD39 compared to classically activated macrophages. The CD39 inhibitor POM-1 and adenosine deaminase (ADA) diminished some of the immunosuppressive functions of CD14 high CD163 high CD39 high macrophages, such as IL-10 secretion. We identified the cytokine IL-27, secreted by tumor-infiltrating neutrophils, located close to infiltrating CD163 C macrophages, as a major rheostat of CD39 expression and consequently, on the acquisition of immunoregulatory properties by macrophages. Accordingly, the depletion of IL-27 downregulated CD39 and PD-L1 expression as well as IL-10 secretion by M-CSF-macrophages. Collectively, these data suggest that CD39, drived by IL-27 and CD115 ligands in ovarian cancer, maintains the immunosuppressive phenotype of TAM. This work brings new information on the acquisition of immunosuppressive properties by tumor-infiltrating macrophages.

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Selective A2A adenosine agonist ATL-146e attenuates acute lethal liver injury in mice

Abstract: The present findings suggest that the highly selective adenosine A2A receptor agonist (ATL-146e) prevents endotoxin-induced lethal liver injury by suppression of TNF-alpha secretion.

Cited by 19 publications

References 17 publications

Activated hepatic stellate cells upregulate transcription of ecto-5′-nucleotidase/CD73 via specific SP1 and SMAD promoter elements

Activated hepatic stellate cells upregulate transcription of ecto-5′-nucleotidase/CD73 via specific SP1 and SMAD promoter elements

Expression of mediators of purinergic signaling in human liver cell lines

The ecto-ATPDase CD39 is involved in the acquisition of the immunoregulatory phenotype by M-CSF-macrophages and ovarian cancer tumor-associated macrophages: Regulatory role of IL-27

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