Mizumoto N, Kumamoto T, Robson SC, Sévigny J, Matsue H, Enjyoji K et al.CD39 is the dominant Langerhans cell-associated ecto-NTPDase: modulatory roles in inflammation and immune responsiveness. Nat Med 8:358-365

Harvard University, Cambridge, Massachusetts, United States
Nature Medicine (Impact Factor: 27.36). 05/2002; 8(4):358-65. DOI: 10.1038/nm0402-358
Source: PubMed


CD39, the endothelial ecto-nucleoside triphosphate diphosphohydrolase (NTPDase), regulates vascular inflammation and thrombosis by hydrolyzing ATP and ADP. Although ecto-NTPDase activities have been used as a marker of epidermal dendritic cells (DCs) known as Langerhans cells, the identity and function of these activities remain unknown. Here we report that Langerhans cells in CD39-/- mice express no detectable ecto-NTPDase activity. Irritant chemicals triggered rapid ATP and ADP release from keratinocytes and caused exacerbated skin inflammation in CD39-/- mice. Paradoxically, T cell-mediated allergic contact hypersensitivity was severely attenuated in CD39-/- mice. As to mechanisms, T cells increased pericellular ATP concentrations upon activation, and CD39-/- DCs showed ATP unresponsiveness (secondary to P2-receptor desensitization) and impaired antigen-presenting capacity. Our results show opposing outcomes of CD39 deficiency in irritant versus allergic contact dermatitis, reflecting its diverse roles in regulating extracellular nucleotide-mediated signaling in inflammatory responses to environmental insults and DC-T cell communication in antigen presentation.

Download full-text


Available from: Jean Sévigny, Apr 15, 2014
  • Source
    • " ) preparation ( Strehler & Totter , 1952 ) , followed by bioluminescent detection of ADP - derived ATP . Using these techniques , extracellular ADP levels were determined in cultured endothelial , lymphoid and tumor cells ( Helenius et al . , 2012 ; Yegutkin et al . , 2011a ) , rat pancreatic juice ( Sorensen et al . , 2003 ) , keratino - cytes ( Mizumoto et al . , 2002 ) , murine plasma ( Enjyoji et al . , 1999 ; Mercier et al . , 2012 ) , and human vitreous fluids ( Loukovaara et al . , 2014 ) . Likewise , using another mixture of enzymes and substrates , another important ATP metabolite , PP i , can be measured in the extracellular fluids DOI : 10 . 3109 / 10409238 . 2014 . 953627 Ectoenzymes contro"
    [Show abstract] [Hide abstract]
    ABSTRACT: Abstract Extracellular nucleotides and nucleosides mediate diverse signaling effects in virtually all organs and tissues. Most models of purinergic signaling depend on functional interactions between distinct processes, including (i) the release of endogenous ATP and other nucleotides, (ii) triggering of signaling events via a series of nucleotide-selective ligand-gated P2X and metabotropic P2Y receptors as well as adenosine receptors and (iii) ectoenzymatic interconversion of purinergic agonists. The duration and magnitude of purinergic signaling is governed by a network of ectoenzymes, including the enzymes of the nucleoside triphosphate diphosphohydrolase (NTPDase) family, the nucleotide pyrophosphatase/phosphodiesterase (NPP) family, ecto-5'-nucleotidase/CD73, tissue-nonspecific alkaline phosphatase (TNAP), prostatic acid phosphatase (PAP) and other alkaline and acid phosphatases, adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP). Along with "classical" inactivating ectoenzymes, recent data provide evidence for the co-existence of a counteracting ATP-regenerating pathway comprising the enzymes of the adenylate kinase (AK) and nucleoside diphosphate kinase (NDPK/NME/NM23) families and ATP synthase. This review describes recent advances in this field, with special emphasis on purine-converting ectoenzymes as a complex and integrated network regulating purinergic signaling in such (patho)physiological states as immunomodulation, inflammation, tumorigenesis, arterial calcification and other diseases. The second part of this review provides a comprehensive overview and basic principles of major approaches employed for studying purinergic activities, including spectrophotometric Pi-liberating assays, high-performance liquid chromatographic (HPLC) and thin-layer chromatographic (TLC) analyses of purine substrates and metabolites, capillary electrophoresis, bioluminescent, fluorometric and electrochemical enzyme-coupled assays, histochemical staining, and further emphasizes their advantages, drawbacks and suitability for assaying a particular catalytic reaction.
    Full-text · Article · Nov 2014 · Critical Reviews in Biochemistry and Molecular Biology
  • Source
    • "In addition, it maintains the blood flow in the absence of prostacyclin and nitric oxide, reducing the risk for thrombosis. CD39 also activates the type II immune response by regulating the expression of cytokines, inducing cell adhesion [22]–[24] and leukocyte migration [25], which reduces inflammation and regulates the immune function, exerting protective effect on the ischemia-reperfusion injury of the heart and brain [26]–[33]. Human CD39 gene comprises an open reading frame encoding about 510 amino acids, of which there are six N-glycosylation sites, 11 cysteine residues and two transmembrane domains [21]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: This study aimed to investigate the influence of low-dose levodopa (L-DOPA) on neuronal cell death under oxidative stress. PC12 cells were treated with L-DOPA at different concentrations. We detected the L-DOPA induced reactive oxygen species (ROS). Meanwhile, MTT and LDH assay were performed to determine the proliferation and growth of PC12 cells with or without ROS scavenger. In addition, after pretreatment with L-DOPA at different concentrations alone or in combination with CD39 inhibitor, PC12 cells were incubated with hydrogen peroxide (H2O2) and the cell viability was evaluated by MTT and LDH assay. In addition, the expression of pCREB and CD39 was detected by immunofluorescence staining and Western blot assay in both cells and rat's brain after L-DOPA treatment. After treatment with L-DOPA for 3 days, the cell proliferation and growth were promoted when the L-DOPA concentration was <30 µM, while cell proliferation was comparable to that in control group when the L-DOPA concentration was >30 µM. Low dose L-DOPA could protect the PC12 cells from H2O2 induced oxidative stress, which was compromised by CD39 inhibitor. In addition, the expression of CD39 and pCREB increased in both PC12 cells and rats' brain after L-DOPA treatment. L-DOPA at different concentrations has distinct influence on proliferation and growth of PC12 cells, and low dose (<30 µM) L-DOPA protects PC12 cells against oxidative stress which might be related to the up-regulation of CD39 and pCREB expression.
    Full-text · Article · Apr 2014 · PLoS ONE
  • Source
    • "To resolve inflammation, the extracellular ATP is degraded by the ectonucleoside triphosphate diphosphohydrolase CD39 expressed on immune cells such as Langerhans cells (LCs) and regulatory T cells (Junger, 2011). Therefore, inflammation is exacerbated in CD39-deficient mice because of increased local ATP concentration (Mizumoto et al., 2002). As receptors for extracellular ATP, P2 purinoceptors comprise P2X1 to P2X7 and act as ATP-gated ion channels (Di Virgilio, 2007). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Mast cells (MCs) mature locally, thus possessing tissue-dependent phenotypes for their critical roles in both protective immunity against pathogens and the development of allergy or inflammation. We previously reported that MCs highly express P2X7, a receptor for extracellular ATP, in the colon but not in the skin. The ATP-P2X7 pathway induces MC activation and consequently exacerbates the inflammation. Here, we identified the mechanisms by which P2X7 expression on MCs is reduced by fibroblasts in the skin, but not in the other tissues. The retinoic-acid-degrading enzyme Cyp26b1 is highly expressed in skin fibroblasts, and its inhibition resulted in the upregulation of P2X7 on MCs. We also noted the increased expression of P2X7 on skin MCs and consequent P2X7- and MC-dependent dermatitis (so-called retinoid dermatitis) in the presence of excessive amounts of retinoic acid. These results demonstrate a unique skin-barrier homeostatic network operating through Cyp26b1-mediated inhibition of ATP-dependent MC activation by fibroblasts.
    Full-text · Article · Apr 2014 · Immunity
Show more