Severe malaria anemia is characterized by inhibited/altered erythropoiesis and presence of hemozoin-(HZ)-laden bone-marrow macrophages. HZ mediates peroxidation of unsaturated fatty acids and production of bioactive aldehydes such as 4-hydroxynonenal (HNE). HZ-laden human monocytes inhibited growth of co-cultivated human erythroid cells and produced HNE that diffused to adjacent cells generating HNE-protein adducts. Co-cultivation with HZ or treatment with low-micromolar HNE inhibited growth of erythroid cells interfering with cell cycle without apoptosis. Following HZ/HNE treatment, two critical proteins in cell cycle regulation, p53 and p21, were increased and the retinoblastoma protein, central regulator of G1-to-S-phase transition, was consequently hypophosphorylated, while GATA-1, master transcription factor in erythropoiesis was reduced. The resultant decreased expression of cyclin A and D2 retarded cell cycle progression in erythroid cells and the K562 cell line. As a second major effect, HZ and HNE inhibited protein expression of crucial receptors (R): transferrinR1, stem cell factorR, interleukin-3R and erythropoietinR. The reduced receptor expression and the impaired cell cycle activity decreased the production of cells expressing glycophorin-A and hemoglobin. Present data confirm the inhibitory role of HZ, identify HNE as one HZ-generated inhibitory molecule and describe molecular targets of HNE in erythroid progenitors possibly involved in erythropoiesis inhibition in malaria anemia.

Inhibition of erythropoiesis in malaria anemia: role of hemozoin and hemozoin-generated 4-hydroxynonenal.

SKOROKHOD, OLEKSII;CAIONE, Luisa;MARROCCO, Tiziana;MIGLIARDI, GIORGIA;BARRERA, VALENTINA;ARESE, Paolo;PIACIBELLO, Vanda;KEILING, BRIGITTE EVELIN
2010-01-01

Abstract

Severe malaria anemia is characterized by inhibited/altered erythropoiesis and presence of hemozoin-(HZ)-laden bone-marrow macrophages. HZ mediates peroxidation of unsaturated fatty acids and production of bioactive aldehydes such as 4-hydroxynonenal (HNE). HZ-laden human monocytes inhibited growth of co-cultivated human erythroid cells and produced HNE that diffused to adjacent cells generating HNE-protein adducts. Co-cultivation with HZ or treatment with low-micromolar HNE inhibited growth of erythroid cells interfering with cell cycle without apoptosis. Following HZ/HNE treatment, two critical proteins in cell cycle regulation, p53 and p21, were increased and the retinoblastoma protein, central regulator of G1-to-S-phase transition, was consequently hypophosphorylated, while GATA-1, master transcription factor in erythropoiesis was reduced. The resultant decreased expression of cyclin A and D2 retarded cell cycle progression in erythroid cells and the K562 cell line. As a second major effect, HZ and HNE inhibited protein expression of crucial receptors (R): transferrinR1, stem cell factorR, interleukin-3R and erythropoietinR. The reduced receptor expression and the impaired cell cycle activity decreased the production of cells expressing glycophorin-A and hemoglobin. Present data confirm the inhibitory role of HZ, identify HNE as one HZ-generated inhibitory molecule and describe molecular targets of HNE in erythroid progenitors possibly involved in erythropoiesis inhibition in malaria anemia.
2010
116
4328
4337
http://bloodjournal.hematologylibrary.org/cgi/reprint/116/20/4328
Skorokhod OA; Caione L; Marrocco T; Migliardi G; Barrera V; Arese P; Piacibello W; Schwarzer E
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/136592
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