Adherent Leukocytes Prevent Adenosine Formation and Impair Endothelial Barrier Function by Ecto-5′-nucleotidase/CD73-dependent Mechanism

Henttinen, Tiina; Jalkanen, Sirpa; Yegutkin, Gennady G.

doi:10.1074/jbc.m300779200

Cited by 62 publications

(60 citation statements)

References 40 publications

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“…AMP is an important intermediate metabolite of ecto-enzymatic ATP metabolism that can be either irreversibly hydrolyzed into adenosine by ecto-5Ј-nucleotidase or regenerated into ATP via ecto-nucleotidase kinase reactions. Concentration of AMP is not a limiting factor, because CD73 functions as a master switch, determining the shift from the ATP-consuming/adenosine-producing pathway to the ATP-generating pathway, and whenever more AMP is needed for adenosine production less ATP is generated (18,33). Moreover, pathological conditions such as hypoxia and tissue injury trigger release of high amounts of AMP (34,35).…”

Section: Discussionmentioning

confidence: 99%

IFN-α Induced Adenosine Production on the Endothelium: A Mechanism Mediated by CD73 (Ecto-5′-Nucleotidase) Up-Regulation

Niemelä

Henttinen

Yegutkin

et al. 2004

The Journal of Immunology

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CD73 (ecto-5′-nucleotidase; EC 3.1.3.5) participates in lymphocyte binding to endothelial cells and converts extracellular AMP into a potent anti-inflammatory substance adenosine. However, the regulation of expression and function of CD73 has remained largely unknown. In this study, we show that IFN-α produces a time- and dose-dependent long-term up-regulation of CD73 on endothelial cells, but not on lymphocytes both at protein and RNA levels. Moreover, CD73-mediated production of adenosine is increased after IFN-α treatment on endothelial cells, resulting in a decrease in the permeability of these cells. Subsequent to induction with PMA, FMLP, dibutyryl cAMP, thrombin, histamine, IL-1β, TNF-α, and LPS, no marked changes in the level of CD73 expression on endothelial cells are observed. We also show that CD73 is up-regulated in vivo on the vasculature after intravesical treatment of urinary bladder cancers with IFN-α. In conclusion, distinct behavior of lymphocyte and endothelial CD73 subsequent to cytokine treatment further emphasizes the existence of cell type-specific mechanisms in the regulation of CD73 expression and function. Overall, these results suggest that IFN-α is a relevant in vivo regulator of CD73 in the endothelial-leukocyte microenvironment in infections/inflammations, and thus has a fundamental role in controlling the extent of inflammation via CD73-dependent adenosine production.

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Section: Discussionmentioning

confidence: 99%

IFN-α Induced Adenosine Production on the Endothelium: A Mechanism Mediated by CD73 (Ecto-5′-Nucleotidase) Up-Regulation

Niemelä

Henttinen

Yegutkin

et al. 2004

The Journal of Immunology

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“…Endothelial cells have high activities of CD39 and CD73 (3,6,7) and thus take care of efficient hydrolysis of ATP/ADP to AMP and adenosine and prevent prothrombotic effect of circulating ADP. In contrast, the lymphoid cells are generally characterized by a counteracting, ATP-regenerating, and adenosine-eliminating phenotype (8) Upon adhesion, the lymphocytes inhibit endothelial ecto-5Ј-nucleotidase and prevent adenosine formation, thus facilitating their transmigration into the tissue (9).…”

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confidence: 99%

ATP-consuming and ATP-generating Enzymes Secreted by Pancreas

Yegutkin

Samburski

Jalkanen

et al. 2006

Journal of Biological Chemistry

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Pancreatic acini release ATP in response to various stimuli, including cholecystokinin octapeptide (CCK-8), as we show in the present study. There were indications that pancreatic juice also contains enzymes that could hydrolyze ATP during its passage through the ductal system. The aim of this study was to determine which ATP-degrading and possibly ATP-generating enzymes were present in pancreatic secretion. For this purpose, pancreatic juice was collected from anesthetized rats stimulated with infusion of CCK-8. Purine-converting activities in juice samples were assayed by TLC using either [ 3 H]AMP to adenosine. Along with highly active hydrolytic enzymes, there were also ATP-generating enzymes in pancreatic juice, adenylate kinase, and NDP kinase, capable of sequentially phosphorylating AMP via ADP to ATP. Activities of nonspecific phosphatases, nucleotide pyrophosphatase/ phosphodiesterases, and adenosine deaminase were negligible. Taken together, CCK-8 stimulation of pancreas causes release of both ATP-consuming and ATP-generating enzymes into pancreatic juice. This newly discovered richness of secreted enzymes underscores the importance of purine signaling between acini and pancreatic ducts lumen and implies regulation of the purine-converting enzymes release.Extracellular ATP and other purines mediate signaling between cells by means of neural transmission, paracrine, and autocrine effects. There are several important steps in this purinergic cascade including release of ATP, interaction with specific P2 purinergic receptors on the target cells, and not the least, ATP-degrading and -converting enzymes, which determine the balance between nucleotides and nucleosides and thus activation of P2 versus P1 (adenosine) receptors.Extracellular nucleotides can be hydrolyzed by a number of enzymes, such as ecto-nucleoside triphosphate diphosphohydrolases from the NTPDase 2 (CD39) family that hydrolyze nucleoside 5Ј-tri-and diphosphates (1). Ecto-nucleotide pyrophosphatase/phosphodiesterases (NPP) have broad substrate specificity and can convert ATP to AMP and PP i (2). Ecto-5Ј-nucleotidases (CD73) further hydrolyze AMP to adenosine, which can be taken up into the cell by specific Na ϩ -dependent nucleoside transporters or converted into inosine by adenosine deaminase. Ecto-alkaline phosphatases have broad action and dephosphorylate 5Ј-tri-, di-, and monophosphates. In addition to these degradation and inactivation pathways, there are also counteracting ATP-generating pathways, which include reverse nucleotide transphosphorylation by adenylate kinase and nucleoside diphosphate kinase (NDPK). These kinases, which play roles in intracellular signaling and in DNA and RNA synthesis among others, are also expressed on surfaces of different cell types and can contribute to nucleotide balance (3).In cardiovascular system and in respiratory epithelia, a number of enzymes handling nucleotides are well characterized. In human blood, soluble NPP, 5Ј-nucleotidase, and adenosine deaminase, as well as adenylate and NDP kinases, c...

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“…In addition, endothelial cells are able to release ATP and AMP locally (2). Nucleoside triphosphate diphosphohydrolase activity was not examined in the present study, since AMP is not a limiting factor for E-5ЈNu (8,18,28).…”

Section: Discussionmentioning

confidence: 99%

Stimulation of ecto-5′-nucleotidase in human umbilical vein endothelial cells by lipopolysaccharide

Man²,

Vanhoutte³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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Li RW, Man RY, Vanhoutte PM, Leung GP. Stimulation of ecto-5Ј-nucleotidase in human umbilical vein endothelial cells by lipopolysaccharide. Am J Physiol Heart Circ Physiol 295: H1177-H1181, 2008. First published July 18, 2008 doi:10.1152/ajpheart.91513.2007.-The involvement of ecto-5Ј-nucleotidase (E-5ЈNu) in the elevation of extracellular adenosine during inflammation is unclear. In the present study, the effect of lipopolysaccharide (LPS), an inflammation inducer, was investigated on E-5ЈNu in human umbilical vein endothelial cells (HUVECs). E-5ЈNu activity was enhanced after a 24 h exposure to LPS. This effect was dose dependent, with an EC 50 of 1.66 ng/ml. At 10 M, the phosphatidylinositol 3-kinase (PI3K) inhibitor LY-294002 abolished the LPS-induced E-5ЈNu activity. However, at 10 M, the NF-B inhibitor ammonium pyrrolidine dithiocarbamate had no effect. LPS upregulated the protein expression but not the messenger RNA expression of E-5ЈNu. The inhibition of E-5ЈNu by 100 M ␣,␤-methylene adenosine-5Ј-diphosphate increased the LPS-induced inflammation, suggesting that E-5ЈNu plays a significant role in reducing inflammation, probably through the generation of adenosine. In conclusion, the experiments indicate that LPS upregulates E-5ЈNu activity in HUVECs through a PI3K-dependent increase in the abundance of E-5ЈNu on cell membranes. Since adenosine is an anti-inflammatory molecule, E-5ЈNu upregulation may be crucial in protecting endothelial cells against inflammatory damage.adenosine; cytokines; inflammation ECTO-5Ј-NUCLEOTIDASE (E-5ЈNu), also known as CD73, is a 70-kDa membrane-bound glycoprotein that is abundant in the endothelium (18). E-5ЈNu extracellularly catalyzes the conversion of purine and pyrimidine ribo-and deoxyribonucleoside monophosphates to their corresponding ribo-and deoxynucleosides. For example, adenosine 5Ј-monophosphate (AMP) is one of the substrates of E-5ЈNu, and adenosine is the corresponding end product (9, 21).Adenosine exerts its effects by interacting with four receptors known as A 1 , A 2A , A 2B , and A 3 receptors (25,27). In addition to its well-known vasodilator and cardioprotective effects (20,23,25), adenosine can also serve as an immunosuppressive agent to minimize tissue damage during inflammation (13,22,25). The stimulation of A 2A receptors downregulates neutrophil functions (25), reduces the recruitment of neutrophil and macrophages to the endothelium (15), and inhibits the production of tumor necrosis factor (TNF)-␣ in peripheral mononuclear white blood cells (4).Endogenous adenosine is increased during inflammation. Since part of the adenosine is derived from the catalytic action of E-5ЈNu, it is plausible that E-5ЈNu activity is subject to change by inflammation and may play an important role in the regulation of the extracellular adenosine level during inflammation. TNF-␣, which is a proinflammatory cytokine, decreases the expression and activity of E-5ЈNu (9), suggesting that less adenosine may be produced to relieve inflammation if E-5ЈNu is downregulated. By ...

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Adherent Leukocytes Prevent Adenosine Formation and Impair Endothelial Barrier Function by Ecto-5′-nucleotidase/CD73-dependent Mechanism

Cited by 62 publications

References 40 publications

IFN-α Induced Adenosine Production on the Endothelium: A Mechanism Mediated by CD73 (Ecto-5′-Nucleotidase) Up-Regulation

IFN-α Induced Adenosine Production on the Endothelium: A Mechanism Mediated by CD73 (Ecto-5′-Nucleotidase) Up-Regulation

ATP-consuming and ATP-generating Enzymes Secreted by Pancreas

Stimulation of ecto-5′-nucleotidase in human umbilical vein endothelial cells by lipopolysaccharide

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