Fliers Eric, Unmehopa Unga A, Alkemade Anneke
Department of Endocrinology and Metabolism F5-168, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
Mol Cell Endocrinol. 2006 Jun 7;251(1-2):1-8. doi: 10.1016/j.mce.2006.03.042. Epub 2006 May 16.
A major change in thyroid setpoint regulation occurs in various clinical conditions such as critical illness and psychiatric disorders. As a first step towards identifying determinants of these setpoint changes, we have studied the distribution and expression of thyroid hormone receptor (TR) isoforms, type 2 and type 3 deiodinase (D2 and D3), and the thyroid hormone transporter monocarboxylate transporter 8 (MCT8) in the human hypothalamus and anterior pituitary. Although the post-mortem specimens used for these studies originated from patients who had died from many different pathologies, the anatomical distribution of these proteins was similar in all patients. D2 enzyme activity was detectable in the infundibular nucleus/median eminence (IFN/ME) region coinciding with local D2 immunoreactivity in glial cells. Additional D2 immunostaining was present in tanycytes lining the third ventricle. Thyrotropin-releasing hormone (TRH) containing neurons in the paraventricular nucleus (PVN) expressed MCT8, TRs as well as D3. These findings suggest that the prohormone thyroxine (T4) is taken up in hypothalamic glial cells that convert T4 into the biologically active triiodothyronine (T3) via the enzyme D2, and that T3 is subsequently transported to TRH producing neurons in the PVN. In these neurons, T3 may either bind to TRs or be metabolized into inactive iodothyronines by D3. By inference, local changes in thyroid hormone metabolism resulting from altered hypothalamic deiodinase or MCT8 expression may underlie the decrease in TRH mRNA reported earlier in the PVN of patients with critical illness and depression. In the anterior pituitary, D2 and MCT8 immunoreactivity occurred exclusively in folliculostellate (FS) cells. Both TR and D3 immunoreactivity was observed in gonadotropes and to a lesser extent in thyrotropes and other hormone producing cell types. Based upon these neuroanatomical findings, we propose a novel model for central thyroid hormone feedback in humans, with a pivotal role for hypothalamic glial cells and pituitary FS cells in processing and activation of T4. Production and action of T3 appear to occur in separate cell types of the human hypothalamus and anterior pituitary.
甲状腺设定点调节的重大变化发生在各种临床状况中，如危重病和精神疾病。作为确定这些设定点变化决定因素的第一步，我们研究了甲状腺激素受体（TR）亚型、2型和3型脱碘酶（D2和D3）以及甲状腺激素转运体单羧酸转运体8（MCT8）在人类下丘脑和垂体前叶中的分布和表达。尽管用于这些研究的尸检标本来自死于多种不同病理状况的患者，但这些蛋白质的解剖分布在所有患者中相似。在漏斗核/正中隆起（IFN/ME）区域可检测到D2酶活性，这与神经胶质细胞中的局部D2免疫反应性一致。第三脑室衬里的伸长细胞中也存在额外的D2免疫染色。室旁核（PVN）中含促甲状腺激素释放激素（TRH）的神经元表达MCT8、TR以及D3。这些发现表明，激素原甲状腺素（T4）在下丘脑神经胶质细胞中被摄取，这些细胞通过D2酶将T4转化为生物活性三碘甲状腺原氨酸（T3），随后T3被转运至PVN中产生TRH的神经元。在这些神经元中，T3可能与TR结合，或者被D3代谢为无活性的碘甲状腺原氨酸。由此推断，下丘脑脱碘酶或MCT8表达改变导致的甲状腺激素代谢局部变化，可能是先前报道的危重病和抑郁症患者PVN中TRH mRNA减少的基础。在垂体前叶，D2和MCT8免疫反应性仅出现在滤泡星状（FS）细胞中。在促性腺激素细胞中观察到TR和D3免疫反应性，在促甲状腺激素细胞和其他激素产生细胞类型中观察到的程度较低。基于这些神经解剖学发现，我们提出了一种人类中枢甲状腺激素反馈的新模型，其中下丘脑神经胶质细胞和垂体FS细胞在T4的加工和激活中起关键作用。T3的产生和作用似乎发生在人类下丘脑和垂体前叶的不同细胞类型中。
