title: Inhibition of erythropoiesis in malaria anemia: role of hemozoin and hemozoin-generated 4-hydroxynonenal.
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 cocultivated human erythroid cells and produced HNE that diffused to adjacent cells generating HNE-protein adducts. Cocultivation with HZ or treatment with low micromolar HNE inhibited growth of erythroid cells interfering with cell cycle without apoptosis. After HZ/HNE treatment, 2 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.
authors.affiliation: Department of Genetics, Biology, and Biochemistry, Laboratory of Cell Therapy, University of Torino Medical School, Torino, Italy.
authors.forename: Oleksii A
authors.initials: OA
authors.lastname: Skorokhod
authors.forename: Luisa
authors.initials: L
authors.lastname: Caione
authors.forename: Tiziana
authors.initials: T
authors.lastname: Marrocco
authors.forename: Giorgia
authors.initials: G
authors.lastname: Migliardi
authors.forename: Valentina
authors.initials: V
authors.lastname: Barrera
authors.forename: Paolo
authors.initials: P
authors.lastname: Arese
authors.forename: Wanda
authors.initials: W
authors.lastname: Piacibello
authors.forename: Evelin
authors.initials: E
authors.lastname: Schwarzer
mesh_terms: D000447:Aldehydes / Q000494:pharmacology*; D000740:Anemia / Q000150:complications* / Q000473:pathology / Q000503:physiopathology*; D015415:Biomarkers / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D018920:Coculture Techniques; D003114:Colony-Forming Units Assay; D019925:Cyclin A / Q000378:metabolism; D056742:Cyclin D2 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D041905:Erythroid Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004920:Erythropoiesis / Q000187:drug effects*; D050982:GATA1 Transcription Factor / Q000378:metabolism; D006021:Glycophorins / Q000378:metabolism; D006420:Hemeproteins / Q000494:pharmacology*; D006454:Hemoglobins / Q000378:metabolism; D006801:Humans; D008288:Malaria / Q000150:complications* / Q000473:pathology / Q000503:physiopathology*; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011971:Receptors, Immunologic / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D000447:Aldehydes; D015415:Biomarkers; D019925:Cyclin A; D056742:Cyclin D2; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050982:GATA1 Transcription Factor; D006021:Glycophorins; D006420:Hemeproteins; D006454:Hemoglobins; D011971:Receptors, Immunologic; D016159:Tumor Suppressor Protein p53; C020753:hemozoin; C027576:4-hydroxy-2-nonenal