Stimulated stromal cells induce gamma-globin gene expression in erythroid cells via nitric oxide production.

Abstract:

OBJECTIVE:We have previously shown that nitric oxide (NO) is involved in the hydroxyurea-induced increase of gamma-globin gene expression in cultured human erythroid progenitor cells and that hydroxyurea increases NO production in endothelial cells via endothelial NO synthase (NOS). We have now expanded those studies to demonstrate that stimulation of gamma-globin gene expression is also mediated by NOS induction in stromal cells within the bone marrow microenvironment. MATERIALS AND METHODS:Using NO analyzer, we measured NO production in endothelial and macrophage cell cultures. In coculture studies of erythroid and stromal cells, we measured globin gene expression during stimulation by NO inducers. RESULTS:Hydroxyurea (30-100 microM) induced NOS-dependent production of NO in human macrophages (up to 1.2 microM). Coculture studies of human macrophages with erythroid progenitor cells also resulted in induction of gamma-globin mRNA expression (up to threefold) in the presence of hydroxyurea. NOS-dependent stimulation of NO by lipopolysaccharide (up to 0.6 microM) has been observed in human macrophages. We found that lipopolysaccharide and interferon-gamma together increased gamma-globin gene expression (up to twofold) in human macrophage/erythroid cell cocultures. Coculture of human bone marrow endothelial cells with erythroid progenitor cells also induced gamma-globin mRNA expression (2.4-fold) in the presence of hydroxyurea (40 microM). CONCLUSION:These results demonstrate an arrangement by which NO and fetal hemoglobin inducers may stimulate globin genes in erythroid cells via the common paracrine effect of bone marrow stromal cells.

journal_name

Exp Hematol

journal_title

Experimental hematology

authors

Cokić VP,Beleslin-Cokić BB,Smith RD,Economou AP,Wahl LM,Noguchi CT,Schechter AN

doi

10.1016/j.exphem.2009.06.009

subject

Has Abstract

pub_date

2009-10-01 00:00:00

pages

1230-7

issue

10

eissn

0301-472X

issn

1873-2399

pii

S0301-472X(09)00250-1

journal_volume

37

pub_type

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