title: Retinoic acid inhibits monocyte to macrophage survival and differentiation.
abstract: Vitamin A metabolites are potent differentiation-inducing agents for myelomonocytic cell lines in vitro and are successfully used for the treatment of patients with acute promyelocytic leukemia. However, little is known about the effects of vitamin A on normal hematopoietic cells. Therefore, we investigated the effect of vitamin A on differentiation and activation of human blood monocytes (MO). Culturing MO for up to 4 days with 9-cis retinoic acid (RA) and all-trans RA but not retinol reduced MO survival, with the remaining cells being morphologically comparable to control cells. Because macrophage colony-stimulating factor (M-CSF) is a well-known survival factor for MO, we measured the M-CSF content of MO culture supernatants using enzyme-linked immunosorbent assay and found that RA suppressed the constitutive secretion of M-CSF. Northern analysis showed that the M-CSF mRNA expression was only slightly reduced by RA treatment, suggesting regulation on the posttranscriptional level. In contrast to MO, M-CSF secretion by MO-derived macrophages (MAC) was not altered by RA, suggesting a differentiation-dependent switch in the responsiveness of MO/MAC to RA. Because M-CSF is not only a survival-promoting but also a differentiation-promoting factor for myeloid cells, we analyzed the effect of RA on MO to MAC maturation. RA suppressed the expression of the maturation-associated antigen carboxypeptidase M (CPM)/MAX.1 at both the protein and mRNA levels and modulated the lipopolysaccharide-stimulated cytokine secretion of MO/MAC. The addition of exogenous M-CSF to RA-containing MO cultures fails to overcome the RA-induced inhibition of MO differentiation. However, the survival rate was improved by exogenous M-CSF. We conclude that RA acts via two different mechanisms on monocyte survival and differentiation: posttranscriptionally by controlling M-CSF secretion, which decreases MO survival, and transcriptionally regulating the expression of differentiation-associated genes. The regulation of M-CSF production may contribute to the antileukemic effect of RA in vivo by reducing autocrine M-CSF production by leukemic cells.
authors.affiliation: Department of Hematology and Oncology, University of Regensburg, Regensburg, Germany. Marina.Kreutz@klinik.uni-regensburg.de
authors.forename: M
authors.initials: M
authors.lastname: Kreutz
authors.forename: J
authors.initials: J
authors.lastname: Fritsche
authors.forename: U
authors.initials: U
authors.lastname: Ackermann
authors.forename: S W
authors.initials: SW
authors.lastname: Krause
authors.forename: R
authors.initials: R
authors.lastname: Andreesen
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D058851:GPI-Linked Proteins; D006801:Humans; D007641:Keratolytic Agents / Q000494:pharmacology*; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D008666:Metalloendopeptidases / Q000096:biosynthesis; D009000:Monocytes / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D014212:Tretinoin / Q000494:pharmacology*
chemical_list: D058851:GPI-Linked Proteins; D007641:Keratolytic Agents; D014212:Tretinoin; D016173:Macrophage Colony-Stimulating Factor; C058479:carboxypeptidase M; D008666:Metalloendopeptidases