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Prepublished online as a Blood First Edition Paper on November 7, 2002; DOI 10.1182/blood-2002-08-2576.
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Blood, 15 March 2003, Vol. 101, No. 6, pp. 2381-2387
PHAGOCYTES
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,
Gábor Bánhegyi,
Tamás Kardon,
Paola Marcolongo,
Piero-Leopoldo Capecchi,
Hans-Joerg Burger,
Angelo Benedetti, and
Rosella Fulceri
From the Dipartimento di Fisiopatologia e Medicina
Sperimentale and Istituto di Semeiotica Medica, Università di
Siena, Siena, Italy; Semmelweis Egyetem Orvosi Vegytani,
Molekuláris Biológiai és Patobiokémiai
Intézete, Budapest, Hungary; and Aventis Pharma Deutschland,
Metabolic Diseases, Frankfurt, Germany.
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 has 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,
N-ethylmaleimide, and
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 (ie, the drug inhibited
phorbol myristate acetate-induced superoxide anion production and
reduced the size of endoplasmic reticulum 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 proapoptotic effect of S3483 was prevented by the inhibition of
nicotinamide adenine dinucleotide phosphate 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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