Ecto-5′-nucleotidase (CD73) regulation by hypoxia-inducible factor-1 mediates permeability changes in intestinal epithelia

Abstract

Circulating or locally released nucleotides are rapidly metabolized by surface ectoenzymes (1). Ecto-5′nucleotidase (CD73) is a membrane-bound glycoprotein that functions to hydrolyze extracellular nucleotides into bioactive nucleoside intermediates (2). Surfacebound CD73 converts AMP to adenosine, which, when released, can activate seven transmembrane-spanning adenosine receptors (3, 4) or can be internalized through dipyridamole-sensitive carriers (5). These pathways have been shown to activate such diverse endpoints as adenine nucleotide recycling during cellular hypoxia (6), stimulation of epithelial electrogenic chloride secretion (responsible for mucosal hydration) (7), regulation of lymphocyte-epithelial adhesion (8), and promotion of endothelial and epithelial barrier function (4). Rather little is known about the regulation of CD73, and whether regulated expression provides a physiologic role. A number of studies have suggested that CD73 contributes to the protective aspects of adenine nucleotide metabolism during hypoxia and ischemia (9). For example, brief periods of ischemia preceding sustained ischemia, termed ischemic preconditioning, appear to result in large part from adenosine metabolism via increased CD73 activity (9). Increased CD73 activity in ischemic preconditioning has been attributed to adenosine receptor activation, protein kinase C activation, and α 1-adrenoreceptor activation (10). Few studies have addressed whether the CD73 gene is transcriptionally regulated. The cloned CD73 gene promoter contains a cAMP response element (CRE) (11), i.e., consensus DNA

Adenosine A2A receptors promote collagen production by a Fli1- and CTGF-mediated mechanism

“…In particular, hypoxia up-regulates CTGF expression through activation of HIF-1α in dermal fibroblasts from scleroderma patients, and thereby contributes to the progression of skin fibrosis [35]. In this respect, as a critical mediator during hypoxia, the actions of adenosine are potentiated by HIF, which has been shown to stimulate the production of extracellular adenosine [36,37], and suppresses both adenosine uptake into the intracellular compartment and its intracellular metabolism [36,38,39] (reviewed in [40]). In fact, although HIF-1α has been shown to up-regulate A 2B R during conditions of hypoxia [39] suggesting a role for the A 2B R in tissue protection [41][42], the A 2A R may likely contribute to the role of adenosine in ischemic settings [39,42].…”

Prostaglandin E2-mediated adenosinergic effects on CD14+cells: Self-amplifying immunosuppression in cancer

“…11 Mouse peritoneal macrophages may also co-express these enzymes, 12 whereas healthy non-activated human blood monocytes and macrophages have abundant expression of CD39 but not CD73 on the cell surface. 13,14 Ectonucleotidase expression can be controlled by the microenvironment; e.g., CD39 expression is regulated by IL-27 in ovarian cancer, 15 while CD73 is upregulated by hypoxia on epithelial cells 16 by TGFb on murine leukocytes 17 and by signal-transducer and activator of transcription-3 (STAT3) activation on murine Th17 cells. 10 Endothelial cells were observed to respond to increased intracellular cAMP levels via an adenosine-mediated paracrine pathway leading to CD73 upregulation.…”

Hypoxia-Inducible Factor/MAZ-Dependent Induction of Caveolin-1 Regulates Colon Permeability through Suppression of Occludin, Leading to Hypoxia-Induced Inflammation

“…HIF signaling is essential for maintaining iron homeostasis during iron deprivation, regulating the intestinal inflammatory response in colitis, and increasing colon cancer progression. Studies assessing the overlapping and distinct roles of HIF1␣ and HIF2␣ demonstrate that HIF1␣ protects the epithelial barrier from acute and chronic intestinal inflammation by activating expression of a large set of barrier protective genes, such as CD55, intestinal trefoil factors, MUC3, and CD73 (6)(7)(8). Disruption of intestinal epithelial HIF1␣ leads to increased injury and inflammation, whereas activation of HIF signaling decreases injury and inflammation in acute models of colitis (9)(10)(11)(12).…”