Differentiation of functional dendritic cells and macrophages from human peripheral blood monocyte precursors is dependent on expression of p21 (WAF1/CIP1) and requires iron

Joan L. Kramer, Ioannis Baltathakis, Orlando S.F. Alcantara, David H. Boldt

Research output: Contribution to journalArticlepeer-review

43 Scopus citations

Abstract

Iron is required for monocyte/macrophage differentiation of HL-60 leukaemia cells. Differentiation requires induction of the cyclin-dependent kinase inhibitor p21 (WAF1/CIP1), and cell cycle arrest at the G1/S checkpoint. With iron depletion, p21 induction and differentiation are blocked. To establish the roles of iron and p21 in normal monocyte/macrophage differentiation, we examined generation of dendritic cells (DCs) and macrophages from peripheral monocytes. Monocytes were cultured with interleukin 4 and granulocyte-macrophage colony-stimulating factor (GM-CSF), then treated with lipopolysaccharide to produce DCs or with M-CSF to produce macrophages. Iron deprivation was induced by desferrioxamine (DF). Monocyte-derived DCs had characteristic phenotype and morphology, and stimulated proliferation of naïve allogeneic T lymphocytes. In contrast, DCs generated under iron deprivation were phenotypically undifferentiated and did not stimulate T cells. Similarly, macrophages expressed a characteristic phenotype and morphology, and phagocytosed latex beads, but macrophages generated under iron deprivation failed to develop a mature phenotype and had impaired phagocytosis. Iron deprivation blocked induction of p21 (WAF1/CIP1) expression in both DC and macrophage cultures. Furthermore, p21 antisense oligonucleotides, but not sense oligonucleotides, inhibited both DC and macrophage differentiation. These data indicate that a key role of iron in haematopoiesis is to support induction of p21 which, in turn, is required for DC and macrophage differentiation.

Original languageEnglish (US)
Pages (from-to)727-734
Number of pages8
JournalBritish Journal of Haematology
Volume117
Issue number3
DOIs
StatePublished - 2002

Keywords

  • Dendritic cells
  • Haematopoiesis
  • Iron
  • Macrophages
  • p21(WAF1/CIP1)

ASJC Scopus subject areas

  • Hematology

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