Sinclair A J, Onyimba C U, Khosla P, Vijapurapu N, Tomlinson J W, Burdon M A, Stewart P M, Murray P I, Walker E A, Rauz S
Department of Neuroscience, Queen Elizabeth Hospital, University Hospital Birmingham NHS Foundation Trust, Edgbaston, Birmingham, UK.
J Neuroendocrinol. 2007 Aug;19(8):614-20. doi: 10.1111/j.1365-2826.2007.01569.x.
The epithelial cells of the choroid plexus (CP) are responsible for cerebrospinal fluid (CSF) secretion into the ventricles of the brain. The balance between CSF production and drainage, in part, facilitates a normal intracranial pressure. The secretion of Na(+) and anions by the CP creates an osmotic gradient driving water into the ventricles. This is opposite to classical Na(+) transporting tissues, such as the kidney, where Na(+) and water reabsorption is mediated by 11beta-hydroxysteroid dehydrogenase type 2 that protects the mineralocorticoid receptor by abrogating active cortisol to inactive cortisone. In the human ocular ciliary epithelium, Na(+) and water secretion is dependent on a novel mediator of ciliary epithelial Na(+) transport, 11beta-HSD type 1 (11beta-HSD1), that generates intraocular cortisol. In a mechanism analogous to that of the embryologically related ocular ciliary epithelium, we propose that autocrine regulation of intracranial cortisol is dependent on 11beta-HSD1 expression in the CP epithelial cells. By conducting immunolocalisation studies on brains from New Zealand White Albino rabbits, we defined the expression of 11beta-HSD1 in the secretory CP epithelial cells. Enzyme assays performed on intact rabbit CP whole tissue explants confirmed predominant 11beta-HSD1 activity, generating cortisol that was inhibited by glycyrrhetinic acid (an 11beta-HSD inhibitor). Using the real time-polymerase chain reaction, rabbit CP tissue was found to express levels of 11beta-HSD1, glucocorticoid receptor alpha and serum and glucocorticoid-regulated kinase 1 mRNA comparable to that expressed in rabbit ocular ciliary body, thereby highlighting the similarity between these two tissues. Furthermore, an enzyme-linked immunosorbent assay of rabbit CSF revealed a median cortisol concentration of 1.7 nmol/l (range 1.4-4.3 nmol/l, n = 9). Our data have identified a functional 11beta-HSD1 within the CP, mediating intracranial cortisol bioavailability. Expression of 11beta-HSD1 may be fundamental in the regulation of CSF secretion and the local generation of cortisol may represent a pathophysiological mechanism underlying cortisol-dependent neuroendocrine diseases.
脉络丛（CP）的上皮细胞负责将脑脊液（CSF）分泌到脑室中。脑脊液生成与引流之间的平衡在一定程度上有助于维持正常的颅内压。脉络丛分泌钠离子和阴离子，形成一个渗透梯度，驱使水分进入脑室。这与经典的钠离子转运组织（如肾脏）相反，在肾脏中，钠离子和水的重吸收由2型11β-羟基类固醇脱氢酶介导，该酶通过将活性皮质醇转化为无活性的可的松来保护盐皮质激素受体。在人类眼睫状体上皮中，钠离子和水的分泌依赖于一种新型的睫状体上皮钠离子转运介质，即1型11β-羟基类固醇脱氢酶（11β-HSD1），它能产生眼内皮质醇。在一种类似于胚胎学上相关的眼睫状体上皮的机制中，我们提出颅内皮质醇的自分泌调节依赖于脉络丛上皮细胞中11β-HSD1的表达。通过对新西兰白兔大脑进行免疫定位研究，我们确定了11β-HSD1在分泌性脉络丛上皮细胞中的表达。对完整的兔脉络丛全组织外植体进行的酶活性测定证实了主要的11β-HSD1活性，产生的皮质醇受到甘草次酸（一种11β-HSD抑制剂）的抑制。使用实时聚合酶链反应，发现兔脉络丛组织中11β-HSD1、糖皮质激素受体α以及血清和糖皮质激素调节激酶1的mRNA表达水平与兔眼睫状体中的表达水平相当，从而突出了这两种组织之间的相似性。此外，对兔脑脊液进行的酶联免疫吸附测定显示，皮质醇的中位浓度为1.7 nmol/l（范围为1.4 - 4.3 nmol/l，n = 9）。我们的数据确定了脉络丛中存在功能性上的11β-HSD1，它介导颅内皮质醇的生物利用度。11β-HSD1的表达可能是脑脊液分泌调节的基础，而局部产生的皮质醇可能代表了依赖皮质醇的神经内分泌疾病的病理生理机制。
