Department of Medicine (G.W., P.S.S., S.S.N., R.M.L.), Division of Endocrinology, Diabetes and Metabolism, Tupper Research Institute, Tufts Medical Center, and Department of Neuroscience (R.M.L.), Tufts University School of Medicine, Boston, Massachusetts 02111; Thyroid Section (J.W.H., P.R.L.), Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital, Boston, Massachusetts 02115; and School of Biological Sciences (P.S.S.), National Institute of Science Education and Research, Institute of Physics Campus, PO Sainik School, Bhubaneswar-751005, India.
Endocrinology. 2014 May;155(5):2009-19. doi: 10.1210/en.2013-2154. Epub 2014 Mar 6.
Thyroid hormone regulates immune functions and has antiinflammatory effects. In promoter assays, the thyroid hormone-activating enzyme, type 2 deiodinase (D2), is highly inducible by the inflammatory transcription factor nuclear factor-κ B (NF-κB), but it is unknown whether D2 is induced in a similar fashion in vivo during inflammation. We first reexamined the effect of bacterial lipopolysaccharide (LPS) on D2 expression and NF-κB activation in the rat and mouse brain using in situ hybridization. In rats, LPS induced very robust D2 expression in normally non-D2-expressing cells in the leptomeninges, adjacent brain blood vessels, and the choroid plexus. These cells were vimentin-positive fibroblasts and expressed the NF-κB activation marker, inhibitor κ B-α mRNA, at 2 hours after injection, before the increase in D2 mRNA. In mice, LPS induced intense D2 expression in the choroid plexus but not in leptomeninges, with an early expression peak at 2 hours. Moderate D2 expression along numerous brain blood vessels appeared later. D2 and NF-κB activation was induced in tanycytes in both species but with a different time course. Enzymatic assays from leptomeningeal and choroid plexus samples revealed exceptionally high D2 activity in LPS-treated rats and Syrian hamsters and moderate but significant increases in mice. These data demonstrate the cell type-specific, highly inducible nature of D2 expression by inflammation, and NF-κB as a possible initiating factor, but also warrant attention for species differences. The results suggest that D2-mediated T₃ production by fibroblasts regulate local inflammatory actions in the leptomeninges, choroid plexus and brain blood vessels, and perhaps also in other organs.
甲状腺激素调节免疫功能并具有抗炎作用。在启动子分析中，甲状腺激素激活酶，2 型脱碘酶（D2），可被炎症转录因子核因子-κB（NF-κB）高度诱导，但在体内炎症过程中 D2 是否以类似方式诱导尚不清楚。我们首先使用原位杂交重新检查了细菌脂多糖（LPS）对大鼠和小鼠脑中 D2 表达和 NF-κB 激活的影响。在大鼠中，LPS 在软脑膜、相邻脑血管和脉络丛中正常不表达 D2 的细胞中诱导了非常强烈的 D2 表达。这些细胞是波形蛋白阳性成纤维细胞，并在注射后 2 小时表达 NF-κB 激活标记物，IκB-α mRNA，在 D2 mRNA 增加之前。在小鼠中，LPS 在脉络丛中诱导强烈的 D2 表达，但不在软脑膜中，表达峰值出现在 2 小时。后来，许多脑血管中出现中度 D2 表达。在两种物种中，D2 和 NF-κB 激活均诱导于室管膜细胞中，但具有不同的时间过程。来自软脑膜和脉络丛样本的酶分析显示，LPS 处理的大鼠和叙利亚仓鼠中 D2 活性异常高，而小鼠中则适度但显著增加。这些数据表明炎症诱导 D2 表达的细胞类型特异性和高度诱导性，NF-κB 可能是一个起始因素，但也需要注意物种差异。结果表明，成纤维细胞中 D2 介导的 T3 产生可调节软脑膜、脉络丛和脑血管中的局部炎症作用，也许还可调节其他器官中的作用。
