Insights into thymic purine metabolism and adenosine deaminase deficiency revealed by transgenic mice overexpressing ecto-5'-nucleotidase (CD73).

Resta, Regina; Hooker, Scott W.; Laurent, Aletha B.; Rahman, Saifur; Franklin, M; Knudsen, Thomas B.; Nadon, Nancy L.; Thompson, Linda F.

doi:10.1172/jci119211

Cited by 44 publications

(26 citation statements)

References 35 publications

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“…Thymic lobes were harvested at various times after the initiation of FTOCs and single cell suspensions were made. Cell cycle analysis was performed by staining with PI as described previously (28). PI staining was evaluated with a FACScan utilizing doublet discrimination software.…”

Section: Methodsmentioning

confidence: 99%

Metabolites from apoptotic thymocytes inhibit thymopoiesis in adenosine deaminase–deficient fetal thymic organ cultures

Thompson¹,

Wiele²,

Laurent³

et al. 2000

J. Clin. Invest.

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Murine fetal thymic organ culture was used to investigate the mechanism by which adenosine deaminase (ADA) deficiency causes T-cell immunodeficiency. C57BL/6 fetal thymuses treated with the specific ADA inhibitor 2′-deoxycoformycin exhibited features of the human disease, including accumulation of dATP and inhibition of S-adenosylhomocysteine hydrolase enzyme activity. Although T-cell receptor (TCR) Vβ gene rearrangements and pre-TCR-α expression were normal in ADA-deficient cultures, the production of αβ TCR + thymocytes was inhibited by 95%, and differentiation was blocked beginning at the time of β selection. In contrast, the production of γδ TCR + thymocytes was unaffected. Similar results were obtained using fetal thymuses from ADA gene-targeted mice. Differentiation and proliferation were preserved by the introduction of a bcl-2 transgene or disruption of the gene encoding apoptotic protease activating factor-1. The pan-caspase inhibitor carbobenzoxy-Val-Ala-Asp-fluoromethyl ketone also significantly lessened the effects of ADA deficiency and prevented the accumulation of dATP. Thus, ADA substrates accumulate and disrupt thymocyte development in ADA deficiency. These substrates derive from thymocytes that undergo apoptosis as a consequence of failing to pass developmental checkpoints, such as β selection.

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Section: Methodsmentioning

confidence: 99%

Metabolites from apoptotic thymocytes inhibit thymopoiesis in adenosine deaminase–deficient fetal thymic organ cultures

Thompson¹,

Wiele²,

Laurent³

et al. 2000

J. Clin. Invest.

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“…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-endothelial adhesion (8), and promotion of endothelial barrier function (4). Targeted overexpression of lymphocyte CD73 revealed that increased adenosine resultant from enhanced CD73 expression contributes to thymocyte apoptosis in adenosine deaminase deficiency (9).…”

mentioning

confidence: 99%

Regulation of Endothelial CD73 by Adenosine: Paracrine Pathway for Enhanced Endothelial Barrier Function

Narravula

Lennon

Mueller

et al. 2000

The Journal of Immunology

109

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During episodes of inflammation, multiple cell types release adenine nucleotides in the form of ATP, ADP, 5′-AMP, and adenosine. In particular, following activation, polymorphonuclear leukocytes release larger quantities of 5′-AMP. Extracellular 5′-AMP is metabolized to adenosine by surface-expressed 5′-ectonucleotidase (CD73). Adenosine liberated by this process activates surface adenosine A2B receptors, results in endothelial junctional reorganization, and promotes barrier function. We hypothesized that adenosine signaling to endothelia provides a paracrine loop for regulated expression of CD73 and enhanced endothelial barrier function. Using an in vitro microvascular endothelial model, we investigated the influence of 5′-AMP; adenosine; and adenosine analogues on CD73 transcription, surface expression, and function. Initial experiments revealed that adenosine and adenosine analogues induce CD73 mRNA (RT-PCR), surface expression (immunoprecipitation of surface biotinylated CD73), and function (HPLC analysis of etheno-AMP conversion to ethenoadenosine) in a time- and concentration-dependent fashion. Subsequent studies revealed that similar exposure conditions increase surface protein through transcriptional induction of CD73. Analysis of DNA-binding activity by EMSA identified a functional role for CD73 cAMP response element and, moreover, indicated that multiple cAMP agonists induce transcriptional activation of functional CD73. Induced CD73 functioned to enhance 5′-AMP-mediated promotion of endothelial barrier (measured as a paracellular flux of 70-kDa FITC-labeled tracer). These results provide an example of transcriptional induction of enzyme (CD73) by enzymatic product (adenosine) and define a paracrine pathway for the regulated expression of vascular endothelial CD73 and barrier function.

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“…Phorbol esters regulate adenosine deaminase mRNA in human thymocytes [344]. Studies of transgenic mice over-expressing CD73, suggest that adenosine accumulation may play a role in adenosine deaminase-deficiency severe combined immunodeficiency [442]. It is known that the thymus and other lymphoid tissues react to nutritional disorders more rapidly than most other organs.…”

Section: Thymusmentioning

confidence: 99%

Purinergic signalling in endocrine organs

Burnstock

2013

Purinergic Signalling

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There is widespread involvement of purinergic signalling in endocrine biology. Pituitary cells express P1, P2X and P2Y receptor subtypes to mediate hormone release. Adenosine 5′-triphosphate (ATP) regulates insulin release in the pancreas and is involved in the secretion of thyroid hormones. ATP plays a major role in the synthesis, storage and release of catecholamines from the adrenal gland. In the ovary purinoceptors mediate gonadotrophin-induced progesterone secretion, while in the testes, both Sertoli and Leydig cells express purinoceptors that mediate secretion of oestradiol and testosterone, respectively. ATP released as a cotransmitter with noradrenaline is involved in activities of the pineal gland and in the neuroendocrine control of the thymus. In the hypothalamus, ATP and adenosine stimulate or modulate the release of luteinising hormone-releasing hormone, as well as arginine-vasopressin and oxytocin. Functionally active P2X and P2Y receptors have been identified on human placental syncytiotrophoblast cells and on neuroendocrine cells in the lung, skin, prostate and intestine. Adipocytes have been recognised recently to have endocrine function involving purinoceptors.

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Insights into thymic purine metabolism and adenosine deaminase deficiency revealed by transgenic mice overexpressing ecto-5'-nucleotidase (CD73).

Cited by 44 publications

References 35 publications

Metabolites from apoptotic thymocytes inhibit thymopoiesis in adenosine deaminase–deficient fetal thymic organ cultures

Metabolites from apoptotic thymocytes inhibit thymopoiesis in adenosine deaminase–deficient fetal thymic organ cultures

Regulation of Endothelial CD73 by Adenosine: Paracrine Pathway for Enhanced Endothelial Barrier Function

Purinergic signalling in endocrine organs

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