Mountford J C, Bunce C M, Hughes S V, Drayson M T, Webb D, Brown G, Hewison M
Department of Medicine, University of Birmingham, United Kingdom.
Exp Hematol. 1999 Mar;27(3):451-60. doi: 10.1016/s0301-472x(98)00078-2.
Hormones such as 1 alpha, 25-dihydroxy vitamin D3 (D3), all-trans retinoic acid, and 9-cis retinoic acid stimulate differentiation of myeloid progenitor cells via their interaction with specific hormone receptors. However, the sensitivity of cells to these agents is not merely governed by the expression of their receptors and the availability of ligand to bind them. Recent studies from our group suggested that the actions of D3 and retinoids on myelopoiesis also are influenced by endogenous mechanisms involving other steroid hormones. In this study we examined the influence of local estrogen metabolism on the differentiation of HL60 cells and normal primitive myeloid progenitor cells. Quantitative thin-layer chromatography (TLC) analyses showed that HL60 and normal cells are able to generate estrone (E1) from estradiol (E2). Neither cell population generated significant amounts of E2 from E1. Reverse transcriptase polymerase chain reaction and Northern analyses confirmed that normal and leukemic myeloid progenitor cells expressed mRNA for the type I and IV isoforms of 17 beta-hydroxysteroid dehydrogenase. Conversion of E2 to E1 was upregulated within 24 hours when HL60 cells were treated with either all-trans retinoic acid or D3 at doses that induce their differentiation toward neutrophils or monocytes, respectively. Similarly, D3-induced monocyte differentiation of normal myeloid progenitor cells was associated with increased capacity to generate E1 from E2. When HL60 cells or normal myeloid progenitor cells were exposed to exogenous E1 they became more sensitive to the differentiation-inducing effects of D3. Data presented provide further evidence for the local modulation of myelopoiesis by intracrine mechanisms. In particular, our findings suggest that local metabolism of steroids by normal as well as leukemic myeloid cells influences their responsiveness to D3 and retinoids.
1α,25 - 二羟基维生素D3（D3）、全反式维甲酸和9 - 顺式维甲酸等激素通过与特定激素受体相互作用刺激髓系祖细胞分化。然而，细胞对这些因子的敏感性不仅取决于其受体的表达以及与之结合的配体的可用性。我们小组最近的研究表明，D3和类视黄醇对骨髓生成的作用也受涉及其他类固醇激素的内源性机制影响。在本研究中，我们检测了局部雌激素代谢对HL60细胞和正常原始髓系祖细胞分化的影响。定量薄层色谱（TLC）分析表明，HL60细胞和正常细胞能够将雌二醇（E2）转化为雌酮（E1）。两种细胞群体均不能从E1大量生成E2。逆转录酶聚合酶链反应和Northern分析证实，正常和白血病髓系祖细胞表达17β - 羟基类固醇脱氢酶I型和IV型同工型的mRNA。当HL60细胞分别用诱导其向中性粒细胞或单核细胞分化的剂量的全反式维甲酸或D3处理时，E2向E1的转化在24小时内上调。同样，D3诱导的正常髓系祖细胞向单核细胞的分化与从E2生成E1的能力增加有关。当HL60细胞或正常髓系祖细胞暴露于外源性E1时，它们对D3的分化诱导作用变得更敏感。所呈现的数据为通过内分泌机制对骨髓生成进行局部调节提供了进一步证据。特别是，我们的研究结果表明，正常和白血病髓系细胞对类固醇的局部代谢影响它们对D3和类视黄醇的反应性。
