Laboratory of Neuroendocrinology, Rockefeller University, New York, New York 10065, USA.
Glia. 2010 Aug;58(10):1257-66. doi: 10.1002/glia.21007.
Glucocorticoids are potent regulators of inflammation exerting permissive, stimulatory, and suppressive effects. Glucocorticoid access to intracellular receptors is regulated by the activity of two distinct enzymes known as 11 beta-hydroxysteroid dehydrogenase (11 beta HSD) Type 1 and Type 2, which catalyze the activation or deactivation of glucocorticoids. Although expression of these enzymes in major organ systems and their roles in the metabolic effects of glucocorticoids have been described, their role in the inflammatory response has only recently started to be addressed. In this report, we have studied the expression and activity of 11 beta HSD Type 1 and Type 2 in microglia cells. Microglia, the brain's resident macrophages, initiate and orchestrate CNS inflammatory responses. Importantly, activated microglia are implicated in most neurodegenerative conditions, making them key subjects of study. We found that microglia expressed 11 beta HSD-1, but not 11 beta HSD-2, both in ex vivo FACS-sorted adult cells and in vitro primary cultures. 11 beta HSD-1 expression was increased in LPS-activated microglia. Moreover, 11 beta HSD-1 catalyzed the metabolic conversion of 11-dehydro-corticosterone into corticosterone (CORT), which potently reduced cytokine production in activated microglia. We propose that 11 beta HSD-1 may provide microglia with an intrinsic mechanism to autoregulate and inhibit proinflammatory mediator production through CORT formation.
糖皮质激素是强有力的炎症调节因子，发挥许可、刺激和抑制作用。糖皮质激素进入细胞内受体的过程受到两种不同酶的活性调节，这两种酶分别被称为 11β-羟类固醇脱氢酶（11β-HSD）1 型和 2 型，它们催化糖皮质激素的激活或失活。尽管这些酶在主要器官系统中的表达及其在糖皮质激素代谢作用中的作用已被描述，但它们在炎症反应中的作用最近才开始被研究。在本报告中，我们研究了 11β-HSD 1 型和 2 型在小胶质细胞中的表达和活性。小胶质细胞是大脑的固有巨噬细胞，启动并协调中枢神经系统的炎症反应。重要的是，激活的小胶质细胞与大多数神经退行性疾病有关，因此成为研究的关键对象。我们发现小胶质细胞表达 11β-HSD-1，但不表达 11β-HSD-2，无论是在体外 FACS 分选的成年细胞中还是在体外原代培养中。LPS 激活的小胶质细胞中 11β-HSD-1 的表达增加。此外，11β-HSD-1 催化 11-去氢皮质酮向皮质酮（CORT）的代谢转化，CORT 强烈抑制激活的小胶质细胞中细胞因子的产生。我们提出，11β-HSD-1 可能为小胶质细胞提供了一种内在机制，通过 CORT 形成来自我调节并抑制促炎介质的产生。
