Gottfried-Blackmore Andres, Sierra Amanda, Jellinck Peter H, McEwen Bruce S, Bulloch Karen
Laboratory of Neuroendocrinology, Rockefeller University, 1230 York Avenue, New York, NY 10065, United States.
J Steroid Biochem Mol Biol. 2008 Mar;109(1-2):96-107. doi: 10.1016/j.jsbmb.2007.12.013. Epub 2008 Feb 2.
In the CNS, steroid hormones play a major role in the maintenance of brain homeostasis and it's response to injury. Since activated microglia are the pivotal immune cell involved in neurodegeneration, we investigated the possibility that microglia provide a discrete source for the metabolism of active steroid hormones. Using RT-PCR, our results showed that mouse microglia expressed mRNA for 17beta-hydroxysteroid dehydrogenase type 1 and steroid 5alpha-reductase type 1, which are involved in the metabolism of androgens and estrogens. Microglia also expressed the peripheral benzodiazepine receptor and steroid acute regulatory protein; however, the enzymes required for de novo formation of progesterone and DHEA from cholesterol were not expressed. To test the function of these enzymes, primary microglia cultures were incubated with steroid precursors, DHEA and AD. Microglia preferentially produced delta-5 androgens (Adiol) from DHEA and 5alpha-reduced androgens from AD. Adiol behaved as an effective estrogen receptor agonist in neuronal cells. Activation of microglia with pro-inflammatory factors, LPS and INFgamma did not affect the enzymatic properties of these proteins. However, PBR ligands reduced TNFalpha production signifying an immunomodulatory role for PBR. Collectively, our results suggest that microglia utilize steroid-converting enzymes and related proteins to influence inflammation and neurodegeneration within microenvironments of the brain.
在中枢神经系统中，类固醇激素在维持脑内稳态及其对损伤的反应中起主要作用。由于活化的小胶质细胞是参与神经退行性变的关键免疫细胞，我们研究了小胶质细胞是否为活性类固醇激素代谢提供独立来源的可能性。利用逆转录聚合酶链反应（RT-PCR），我们的结果显示小鼠小胶质细胞表达17β-羟类固醇脱氢酶1型和类固醇5α-还原酶1型的信使核糖核酸（mRNA），它们参与雄激素和雌激素的代谢。小胶质细胞还表达外周型苯二氮䓬受体和类固醇急性调节蛋白；然而，从胆固醇从头合成孕酮和脱氢表雄酮（DHEA）所需的酶未表达。为了测试这些酶的功能，将原代小胶质细胞培养物与类固醇前体、DHEA和雄烯二酮（AD）一起孵育。小胶质细胞优先从DHEA产生δ-5雄激素（雄烯二醇），从AD产生5α-还原雄激素。雄烯二醇在神经元细胞中表现为有效的雌激素受体激动剂。用促炎因子脂多糖（LPS）和γ干扰素（INFγ）激活小胶质细胞并不影响这些蛋白质的酶活性。然而，外周型苯二氮䓬受体（PBR）配体减少肿瘤坏死因子α（TNFα）的产生，表明PBR具有免疫调节作用。总的来说，我们的结果表明小胶质细胞利用类固醇转化酶和相关蛋白来影响脑微环境中的炎症和神经退行性变。
