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Blood, Vol. 94 No. 9 (November 1), 1999:
pp. 3169-3177
Granulocyte-Macrophage Colony-Stimulating Factor Induces Expression
of Heparin-Binding Epidermal Growth Factor-Like Growth
Factor/Diphtheria Toxin Receptor and Sensitivity to Diphtheria Toxin in
Human Neutrophils
Fabrizio Vinante,
Martina Marchi,
Antonella Rigo,
Patrizia Scapini,
Giovanni Pizzolo, and
Marco A. Cassatella
From the Department of Clinical and Experimental Medicine, Section of
Hematology, and the Department of Pathology, Section of General
Pathology, University of Verona, Verona, Italy.
Heparin-binding epidermal growth factor-like growth factor (HB-EGF)
is a widely expressed EGF superfamily member that induces mitogenic
and/or chemotactic activities toward different cell types through
binding to EGF receptors 1 or 4. Membrane-bound HB-EGF exerts growth
activity and adhesion capabilities and possesses the unique property of
being the receptor for diphtheria toxin (DT). Using molecular and
functional techniques, we show that human polymorphonuclear
granulocytes (PMN), which did not express HB-EGF in resting conditions,
expressed it at mRNA and protein level, following incubation with
granulocyte-macrophage colony-stimulating factor (GM-CSF). Other
classic agonists for PMN (including lipopolysaccharide, phagocytable
particles, tumor necrosis factor- , or G-CSF) failed to induce
HB-EGF. The effects of GM-CSF on HB-EGF mRNA levels were
concentration-dependent, reached a plateau after 1 to 2 hours of
stimulation, and did not require protein synthesis. After GM-CSF treatment, membrane-bound HB-EGF was detected by flow cytometry. At the
same time, PMN acquired sensitivity to the apoptosis-promoting effect
of DT, which, moreover, specifically suppressed the GM-CSF-induced priming of
formyl-methionyl-leucyl-phenylalanine-stimulated
superoxide anion release. Finally, soluble HB-EGF was detected in the
PMN culture medium by a specific enzyme-linked immunosorbent assay. Thus, we provide evidence that HB-EGF is specifically inducible by
GM-CSF in PMN and represents a novel peptide to be included in the
repertoire of PMN-derived cytokines.
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