INSERM UMR 788, Stéroïdes, neuroprotection et neurogénération, 94275 Le Kremlin-Bicêtre cedex, France.
J Endocrinol. 2011 Feb;208(2):183-92. doi: 10.1677/JOE-10-0218. Epub 2010 Nov 10.
In the brain, 3,5,3'-triiodothyronine, which binds to the thyroid hormone receptor with high affinity, is locally generated from thyroxine by type 2 iodothyronine deiodinase (D2) expressed mainly in astrocytes and tanycytes. We have investigated the effects of bacterial lipopolysaccharide (LPS) on D2 in cultured rat astrocytes. LPS induced D2 activity with a lag-time of 4-8 h and a maximum at 24 h. LPS also promoted D2 mRNA accumulation. Glucocorticoids enhanced both the basal and LPS-stimulated D2 activity and mRNA accumulation. These glucocorticoid effects were blocked by the glucocorticoid receptor antagonist RU486. Our results obtained with different specific signaling pathway inhibitors indicated that D2 induction by LPS required ERK and p38-MAPK signaling pathways. NF-κB inhibitor sulfasalazine blocked the effects of LPS on both D2 activity and mRNA accumulation. Hence, D2 induction by LPS appeared to implicate NF-κB pathway in astrocytes. NF-κB responsiveness of the rat dio2 gene was studied in astrocytes with dio2 5'-flanking region promoter assays. The long form of the dio2 promoter was transactivated by NF-κB. CCAAT/enhancer-binding protein β, which is upregulated by LPS in astrocytes, increased the transcriptional activity of the dio2 promoter in its long or truncated forms containing CCAATs. Our observations, which demonstrate D2 induction by LPS in astrocytes and specify some characteristics of D2 induction mechanism, support the possible implication of brain D2 in adaptative responses to an infectious stress.
在大脑中，与甲状腺激素受体具有高亲和力结合的 3,5,3'-三碘甲状腺原氨酸由主要在星形胶质细胞和室管膜细胞中表达的 2 型碘甲状腺原氨酸脱碘酶 (D2) 从甲状腺素局部生成。我们研究了细菌脂多糖 (LPS) 对培养的大鼠星形胶质细胞中 D2 的影响。LPS 诱导 D2 活性的潜伏期为 4-8 小时，24 小时达到最大值。LPS 还促进了 D2 mRNA 的积累。糖皮质激素增强了 D2 的基础和 LPS 刺激活性和 mRNA 积累。这种糖皮质激素作用被糖皮质激素受体拮抗剂 RU486 阻断。我们用不同的特异性信号通路抑制剂获得的结果表明，LPS 诱导 D2 需要 ERK 和 p38-MAPK 信号通路。NF-κB 抑制剂柳氮磺胺吡啶阻断了 LPS 对 D2 活性和 mRNA 积累的影响。因此，LPS 诱导 D2 似乎涉及星形胶质细胞中的 NF-κB 途径。用 dio2 5'-侧翼区启动子测定法研究了 NF-κB 对大鼠 dio2 基因的反应性。Dio2 启动子的长形式被 NF-κB 转激活。CCAAT/增强子结合蛋白 β在星形胶质细胞中被 LPS 上调，增加了 dio2 启动子在其长或截短形式中包含 CCAATs 的转录活性。我们的观察结果表明，LPS 可诱导星形胶质细胞中的 D2，并且明确了 D2 诱导机制的某些特征，这支持了脑 D2 可能参与对感染应激的适应性反应的可能性。
