RETINOIC ACID INHIBITS MONOCYTE TO MACROPHAGE SURVIVAL AND DIFFERENTIATION

A metabolites are potent differentiation-inducing agents for myelomono cytic cell lines in vitro and are successfully used for the treatment of patients with acute promyelocytic leukemia. However, little is know n about the effects of vitamin A on normal hematopoietic cells. Theref ore, we investigated the effect of vitamin A on differentiation and ac tivation 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 comparabl e to control cells. Because macrophage colony-stimulating factor (M-CS F) is a well-known survival factor for MO, we measured the M-CSF conte nt of MO culture supernatants using enzyme-linked immunosorbent assay and found that RA suppressed the constitutive secretion of M-CSF. Nort hern analysis showed that the M-CSF mRNA expression was only slightly reduced by RA treatment, suggesting regulation on the posttranscriptio nal level. In contrast to MO, M-CSF secretion by MO-derived macrophage s (MAC) was not altered by RA, suggesting a differentiation-dependent switch in the responsiveness of MO/MAC to RA. Because M-CSF is not onl y 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 carb oxypeptidase M (CPM)/MAX.1 at both the protein and mRNA levels and mod ulated 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, th e survival rate was improved by exogenous M-CSF. We conclude that RA a cts via two different mechanisms on monocyte survival and differentiat ion: posttranscriptionally by controlling M-CSF secretion, which decre ases MO survival, and transcriptionally regulating the expression of d ifferentiation associated genes. The regulation of M-CSF production ma y contribute to the antileukemic effect of RA in vivo by reducing auto crine M-CSF production by leukemic cells. (C) 1998 by The American Soc iety of Hematology.