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The calcium-regulating hormone 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) is recognized as an immunomodulator. Members of the macrophage-monocyte lineage are targets for 1,25(OH)2D3 action. The hormone enhances the ability of bone marrow-derived macrophages (BMDMs) to produce H2O2, increases the expression of the macrophage specific surface antigen MAC-2, increases the release of tumor necrosis factor-alpha (TNF-alpha), and inhibits BMDM proliferation. In the present study we examine the possibility that estrogen modulates 1,25(OH)2D3 effects on BMDMs. The active form, 17 beta-estradiol, failed to affect any of the BMDM functions by itself. On the other hand, 17 beta-estradiol increased the effects of 1,25(OH)2D3 production by BMDMs and on MAC-2 expression on these cells. The inactive estrogen analog 17 alpha-estradiol was unable to elicit these effects. Moreover, 17 beta-estradiol was unable to elicit these effects. Moreover, 17 beta-estradiol did not affect the lipopolysaccharide (LPS)-induced increase in H2O2 production by BMDMs. Modulation of BMDM proliferation and TNF-alpha release from these cells by 1,25(OH)2D3 were not affected by the estrogen. The experiments were performed with BMDMs harvested from vitamin D-depleted and repleted mice, and always under similar conditions, the various functions were more pronounced in the cells derived from the repleted mice. Our data are consistent with the hypothesis that 17 beta-estradiol modulates the interactions of 1,25(OH)2D3 with BMDMs and consequently is able to affect biological responses to 1,25(OH)2D3 in these cells. We propose that this cell system is a convenient, nontransformed model for studying cellular activities of 1,25(OH)2D3. [ABSTRACT FROM AUTHOR]

1,25-dihydroxyvitamin D3 (1,25(OH)2D3) is a potent inducer of monocytic differentiation of the human promyelocytic leukemia cell line, HL-60. We have noted that 25-hydroxyvitamin D3 (25(OH)D3) in high doses is also capable of promoting monocytic differentiation of this cell line. To test the possibility that the latter activity is due to conversion of 25OHD3 to 1,25(OH)2D3 by HL-60, we exposed HL-60 cells to 25OHD3 and analyzed the products by HPLC and radioreceptor assay. When chromatographed in the traditional solvent system (isopropanol-hexane), a new peak appears which migrates with authentic 1,25(OH)2D3. However, in a solvent system containing dichloromethane, 90% of the peak migrates with another metabolite, 19-Nor-10-Keto-25OHD3 (19-Nor-25OHD3). Production of this metabolite is enhanced by living cells and is synthesized by both virgin HL-60 and those which have undergone differentiation. We next determined if authentic 19-Nor-25OHD3 also promotes differentiation of this cell. As assessed by appearance of the monocyte-specific surface antigen (63D3) and macrophage-specific esterase activity, we find that this metabolite does, in fact, induce monocytic differentiation of HL-60 with a potency of approximately 1/200 that of 1,25(OH)2D3 and similar to that of 25OHD3. In agreement with the effect upon cell maturation, 19-Nor-25OHD3 displaces 3H-1,25(OH)2D3 from its HL-60 receptor with an efficiency comparable to 25OHD3. Hence, HL-60 cells convert 25OHD3 to 19-Nor-25OHD3, and 19-Nor-25OHD3 induces monocytic differentiation of HL-60 with comparable efficiency to its precursor, 25OHD3. [ABSTRACT FROM AUTHOR]

Vitamin D deficient (D) mice show a depressed inflammatory response and both inflammatory peritoneal macrophages and bone marrow polymorphonuclear leukocytes of D mice exhibit a decreased spontaneous migration under agarose. The impaired phagocytic response of peritoneal macrophages from D mice can be corrected by incubation with 1,25-dihydroxyvitamin D and is not affected by interaction with other vitamin D metabolites. Transfer of mice from the D to the D state results in correction of both the inflammatory and the phagocytic response. Intactness of phagocyte function is thus directly dependent on vitamin D metabolism. [ABSTRACT FROM AUTHOR]