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Prepublished online as a Blood First Edition Paper on November 7, 2002; DOI 10.1182/blood-2002-08-2576. This Article Full Text (PDF) All Versions of this Article: 2002-08-2576v1 101/6/2381    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Leuzzi, R. Articles by Fulceri, R. Search for Related Content PubMed PubMed Citation Articles by Leuzzi, R. Articles by Fulceri, R. Social Bookmarking                   What's this? Submitted August 21, 2002 Accepted October 21, 2002 Inhibition of microsomal glucose-6-phosphate transport in human neutrophils results in apoptosis: a potential explanation for neutrophil dysfunction in glycogen storage disease type 1b Rosanna Leuzzi, Gabor Banhegyi, Tamas Kardon, Paola Marcolongo, Piero Leopoldo Capecchi, Hans-Joerg Burger, Angelo Benedetti*, and Rosella Fulceri Dipartimento di Fisiopatologia e Medicina Sperimentale, Universita' di Siena, Siena, Italy Istituto di Semeiotica Medica, Universita' di Siena, Siena, Italy Molekularis Biologiai es Patobiokemiai Intezete, Semmelweis Egyetem Orvosi Vegytani, Budapest, Hungary Metabolic Diseases, Aventis Pharma. Deutschland GmbH, Frankfurt, Germany * Corresponding author; email: benedetti{at}unisi.it. Mutations in the gene of the hepatic glucose-6-phosphate transporter cause glycogen storage disease type 1b. In this disease, the altered glucose homeostasis and liver functions are accompanied by an impairment of neutrophils/monocytes. However, neither the existence of a microsomal glucose-6-phosphate transport, nor the connection between its defect and cell dysfunction have been demonstrated in neutrophils/monocytes. In this study we have characterized the microsomal glucose-6-phosphate transport of human neutrophils and differentiated HL-60 cells. The transport of glucose-6-phosphate was sensitive to the chlorogenic acid derivative S3483, to N-ethylmaleimide and to 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid, known inhibitors of the hepatic microsomal glucose-6-phosphate transporter. A glucose-6-phosphate uptake was also present in microsomes from undifferentiated HL-60 and Jurkat cells, but it was insensitive to S3483. The treatment with S3484 of intact human neutrophils and differentiated HL-60 cells mimicked some leukocyte defects of glycogen storage disease type 1b patients, i.e., the drug inhibited PMA-induced superoxide anion production and reduced the size of ER Ca2+ stores. Importantly, the treatment with S3484 also resulted in apoptosis of human neutrophils and differentiated HL-60 cells, while undifferentiated HL-60 and Jurkat cells were unaffected by the drug. The pro-apoptotic effect of S3483 was prevented by the inhibition of NADPH oxidase or by antioxidant treatment. These results suggest that microsomal glucose-6-phosphate transport has a role in the antioxidant protection of neutrophils, and that the genetic defect of the transporter leads to the impairment of cellular functions and apoptosis. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: G. Banhegyi, M. Csala, and A. Benedetti Hexose-6-phosphate dehydrogenase: linking endocrinology and metabolism in the endoplasmic reticulum J. Mol. Endocrinol., April 1, 2009; 42(4): 283 - 289. [Abstract] [Full Text] [PDF] S. Senesi, P. Marcolongo, I. Manini, R. Fulceri, V. Sorrentino, M. Csala, G. Banhegyi, and A. Benedetti Constant expression of hexose-6-phosphate dehydrogenase during differentiation of human adipose-derived mesenchymal stem cells J. Mol. Endocrinol., September 1, 2008; 41(3): 125 - 133. [Abstract] [Full Text] [PDF] P. Marcolongo, S. Piccirella, S. Senesi, L. Wunderlich, I. Gerin, J. Mandl, R. Fulceri, G. Banhegyi, and A. Benedetti The Glucose-6-Phosphate Transporter-Hexose-6-Phosphate Dehydrogenase-11{beta}-Hydroxysteroid Dehydrogenase Type 1 System of the Adipose Tissue Endocrinology, May 1, 2007; 148(5): 2487 - 2495. [Abstract] [Full Text] [PDF] J.-C. Currie, S. Fortier, A. Sina, J. Galipeau, J. Cao, and B. Annabi MT1-MMP Down-regulates the Glucose 6-Phosphate Transporter Expression in Marrow Stromal Cells: A MOLECULAR LINK BETWEEN PRO-MMP-2 ACTIVATION, CHEMOTAXIS, AND CELL SURVIVAL J. Biol. Chem., March 16, 2007; 282(11): 8142 - 8149. [Abstract] [Full Text] [PDF] T. W. Kuijpers, N. A. Maianski, A. T. J. Tool, G. P. A. Smit, J. P. Rake, D. Roos, and G. Visser Apoptotic neutrophils in the circulation of patients with glycogen storage disease type 1b (GSD1b) Blood, June 15, 2003; 101(12): 5021 - 5024. [Abstract] [Full Text] [PDF]

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