Synergistic effect of verotoxin and interferon-alpha on erythropoiesis.
Previous studies have shown that the verotoxin receptor globotriaosyl ceramide is involved in interferon-alpha (IFN-alpha) signaling pathways. The results of the present study indicate that verotoxin used in combination with IFN-alpha had a direct cytotoxic effect on erythrocyte development by targeting nucleated erythrocyte precursors. Toxin treatment alone had no significant effect on erythropoiesis. However, treatment with 100 ng/ml of verotoxin (VT) in combination with 100 U/ml of IFN-alpha was highly cytotoxic (>90%) to erythroid cells in human cord blood cultures by day 14 post-treatment. The lack of effect on other hematopoietic cells, and the relatively modest decrease in the number of erythroid colonies formed (28%) as a result of IFN-alpha/VT treatment, indicate that the cytotoxicity was targeted specifically toward cells committed to the erythrocyte lineage. IFN-alpha treatment alone did not result in cytotoxicity or a significant reduction in the number of erythroid colonies formed. However, IFN-alpha treatment did result in an increase in the surface expression of verotoxin receptors as determined by flow cytometry following labeling of cells with VT-FITC. Abnormalities in erythrocyte morphology and anemia are associated with infection by verotoxin-producing Escherichia coli such as serotype O157:H7. These symptoms are frequently attributed to passage of erythrocytes through partially occluded blood vessels following toxin-induced damage to endothelial cells. The present results document a synergistic cytotoxic effect of IFN-alpha and verotoxin on erythropoiesis, which could have relevance to clinical infection with verotoxin-producing bacteria.
Maloney
M
M
Department of Biology, Spain College, Atlanta, Georgia 30314-4399, USA. mmaloney@spelman.edu
Lingwood
C
C
D004357:Drug Synergism; D041905:Erythroid Cells / Q000187:drug effects; D015672:Erythroid Precursor Cells / Q000187:drug effects; D004920:Erythropoiesis / Q000187:drug effects*; D005312:Fetal Blood / Q000166:cytology; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology*; D011956:Receptors, Cell Surface / Q000187:drug effects; D022603:Shiga Toxins / Q000494:pharmacology*
D016898:Interferon-alpha; D011956:Receptors, Cell Surface; D022603:Shiga Toxins