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Prepublished online as a Blood First Edition Paper on November 7, 2002; DOI 10.1182/blood-2002-08-2576.
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.
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