cAMP/CREB-mediated Transcriptional Regulation of Ectonucleoside Triphosphate Diphosphohydrolase 1 (CD39) Expression

Liao, Hui; Hyman, Matthew C.; Baek, Amy E.; Fukase, Keigo; Pinsky, David J.

doi:10.1074/jbc.m110.116905

Cited by 81 publications

(64 citation statements)

References 58 publications

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“…Genetic polymorphisms in the ETNP-1 (ectonucleoside triphosphate diphosphohydrolase 1) gene (encoding CD39) that confer a lower CD39 expression have been associated with increased susceptibility to type 2 diabetes (32,33). Cell signaling pathways that regulate CD39 expression on Tregs may also be involved such as the activation of cAMP-induced increase in CD39 mRNA (34). These possibilities are currently being investigated.…”

Section: Discussionmentioning

confidence: 99%

Low expression of CD39 on regulatory T cells as a biomarker for resistance to methotrexate therapy in rheumatoid arthritis

Peres¹,

Liew

Talbot³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

115

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Rheumatoid arthritis (RA) is an inflammatory autoimmune disease characterized by joint destruction and severe morbidity. Methotrexate (MTX) is the standard first-line therapy of RA. However, about 40% of RA patients are unresponsive to MTX treatment. Regulatory T cells (Tregs, CD4 + CD25 + FoxP3 + ) are thought to play an important role in attenuating RA. To investigate the role of Tregs in MTX resistance, we recruited 122 RA patients (53 responsive, R-MTX; 69 unresponsive, UR-MTX) and 33 healthy controls. Three months after MTX treatment, R-MTX but not UR-MTX showed higher frequency of peripheral blood CD39 + CD4 + CD25 + FoxP3 + Tregs than the healthy controls. Tregs produce adenosine (ADO) through ATP degradation by sequential actions of two cell surface ectonucleotidases: CD39 and CD73. Tregs from UR-MTX expressed a lower density of CD39, produced less ADO, and had reduced suppressive activity than Tregs from R-MTX. In a prospective study, before MTX treatment, UR-MTX expressed a lower density of CD39 on Tregs than those of R-MTX or control (P < 0.01). In a murine model of arthritis, CD39 blockade reversed the antiarthritic effects of MTX treatment. Our results demonstrate that MTX unresponsiveness in RA is associated with low expression of CD39 on Tregs and the decreased suppressive activity of these cells through reduced ADO production. Our findings thus provide hitherto unrecognized mechanism of immune regulation in RA and on mode of action of MTX. Furthermore, our data suggest that low expression of CD39 on Tregs could be a noninvasive biomarker for identifying MTX-resistant RA patients.methotrexate | rheumatoid arthritis | adenosine | biomarker | ectonucleotidases

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Section: Discussionmentioning

confidence: 99%

Low expression of CD39 on regulatory T cells as a biomarker for resistance to methotrexate therapy in rheumatoid arthritis

Peres¹,

Liew

Talbot³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

115

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“…Levels of CD39 in murine macrophages (44) and human endothelial cells (45) are both increased by raised cAMP concentrations, and this has been hypothesized to play a role in enhancing vascular antithrombotic properties. As the nucleotide phosphate substrate specificity of CD39 overlaps with SMPDL3A, there exists the potential for complementary cAMP-driven anti-thrombotic roles at the cell surface and in the extracellular milieu for CD39 and SMPDL3A, respectively.…”

Section: Discussionmentioning

confidence: 99%

Sphingomyelin Phosphodiesterase Acid-like 3A (SMPDL3A) Is a Novel Nucleotide Phosphodiesterase Regulated by Cholesterol in Human Macrophages

Traini

Quinn

Sandoval

et al. 2014

Journal of Biological Chemistry

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Background: Cholesterol-loaded macrophages are key mediators of atherosclerosis and demonstrate increased SMPDL3A expression and secretion. Results: SMPDL3A expression is stimulated by cholesterol, liver X receptor ligands, and cAMP and hydrolyzes nucleotide phosphates. Conclusion: SMPDL3A is a nucleotide phosphodiesterase secreted from cholesterol-loaded macrophages. Significance: SMPDL3A possesses a novel enzymatic activity with potential relevance to atherosclerosis.

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“…Intracellular cAMP levels, which are elevated in the absence of ADA, have been reported to increase CD39 expression. 31 Interestingly, ATP has recently been described to influence the suppressive potential and stability of Tregs, which might also interfere with Treg function in ADA deficiency. 32 Although both CD39 and CD73 are rate limiting for extracellular adenosine generation, CD73 is the last component of the ectoenzymatic chain.…”

Section: Discussionmentioning

confidence: 99%

Alterations in the adenosine metabolism and CD39/CD73 adenosinergic machinery cause loss of Treg cell function and autoimmunity in ADA-deficient SCID

Sauer

Brigida

Carriglio

et al. 2012

Blood

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cAMP/CREB-mediated Transcriptional Regulation of Ectonucleoside Triphosphate Diphosphohydrolase 1 (CD39) Expression

Cited by 81 publications

References 58 publications

Low expression of CD39 on regulatory T cells as a biomarker for resistance to methotrexate therapy in rheumatoid arthritis

Low expression of CD39 on regulatory T cells as a biomarker for resistance to methotrexate therapy in rheumatoid arthritis

Sphingomyelin Phosphodiesterase Acid-like 3A (SMPDL3A) Is a Novel Nucleotide Phosphodiesterase Regulated by Cholesterol in Human Macrophages

Alterations in the adenosine metabolism and CD39/CD73 adenosinergic machinery cause loss of Treg cell function and autoimmunity in ADA-deficient SCID

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