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1,25-dihydroxyvitamin D3 production and vitamin D3 receptor expression are
developmentally regulated during differentiation of human monocytes into
macrophages
M Kreutz, R Andreesen, SW Krause, A Szabo, E Ritz and H Reichel
Medizinische Klinik I, Universitat, Freiburg, Germany.
It has been well established that human mononuclear phagocytes have the
capacity to produce 1,25-dihydroxy-vitamin D3 [1,25(OH)3D3] and express the
vitamin D receptor (VDR). However, 1 alpha-hydroxylase activity and VDR
receptor expression during differentiation of monocytes (MO) into mature
macrophages (MAC) have not been previously examined. The in vitro
maturation of blood MO can serve as a model for the in vivo transformation
of immature blood MO into MAC. Here, when cultured in the presence of
serum, MO undergo characteristic changes in morphology, antigenic
phenotype, and functional activity consistent with their differentiation
into MAC. We serially measured 1,25(OH)2D3 and 24,25- dihydroxyvitamin D3
[24,25(OH)2D3] synthesis, specific [3H]-1,25(OH)2D3 binding, and VDR mRNA
levels during in vitro maturation of MO into MAC and correlated these
functions with maturation-associated changes in the phenotype (MAX.1 and
CD71) and secretory repertoire (interleukin-1 beta [IL-1 beta], neopterin)
of the cells. MO showed only little conversion of 25-(OH)D3 into
1,25(OH)2D3 (1.4 +/- 0.4 pmol/10(6) cells/6 h, n = 5) that increased
gradually during maturation into MAC at day 8 of culture (5.3 +/- 4.3
pmol/10(6) cells/6 h, n = 5). Interferon-gamma (IFN-gamma) increased
baseline 1,25(OH)2D3-synthesis approximately twofold during all phases of
differentiation. The time course of increased 1,25(OH)2D3-synthesis
correlated with enhanced secretion of neopterin and expression of MAX.1 and
CD71. The addition of exogenous 1,25(OH)2D3 did not influence constitutive
1,25(OH)2D3 synthesis, but IFN-gamma-stimulated production was suppressed
to baseline levels. Exogenous 1,25(OH)2D3 also stimulated 24,25(OH)2D3
synthesis in freshly isolated MO (from 1.0 +/- 0.8 pmol/6 h to 5.6 +/- 0.9
pmol), whereas matured MAC showed no 24,25(OH)2D3 synthesis. Furthermore,
we examined the expression of the VDR during the differentiation process.
VDR mRNA and protein were constitutively expressed in MO, whereas VDR was
downregulated in mature MAC on both the mRNA and protein levels. Homologous
upregulation of VDR protein by 1,25(OH)2D3 occurred in MO and, to a lesser
degree, in MAC. In contrast, VDR mRNA concentrations were not influenced by
1,25(OH)2D3. Taken together, our results show that MO into MAC
differentiation in vitro is associated with (1) an enhanced capacity to
synthesize 1,25(OH)2D3, (2) a loss of 24,25(OH)2D3-synthesizing activity,
and (3) a decrease in the expression of VDR mRNA and protein. Because
1,25(OH)2D3 was shown to induce differentiation of MO into MAC, our data
sugest an autoregulatory mechanism of MO/MAC generation by 1,25(OH)2D3.
Volume 82,
Issue 4,
pp. 1300-1307,
08/15/1993
Copyright © 1993 by The American Society of Hematology
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