Transforming growth factor-beta signaling alters substrate permeability and tight junction protein expression at the blood-brain barrier during inflammatory pain.
Transforming growth factor-beta signaling alters substrate permeability and tight junction protein expression at the blood-brain barrier during inflammatory pain.
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DOI：
10.1038/jcbfm.2009.32
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发表时间：
2009-06
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影响因子：
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我们的实验室研究表明，λ-卡拉胶（CIP）诱导的外周炎性疼痛可以增加血脑屏障（BBB）的通透性，改变紧密连接（TJ）蛋白的表达，导致血脑屏障功能完整性的改变。然而，参与这种病理生理反应的细胞内信号传导机制尚未阐明。已知转化生长因子(TGF)-β信号通路调节血管完整性和通透性。因此，我们检测了TGF-β信号在CIP大鼠血脑屏障中的作用。在CIP过程中，血清TGF-β1和TGF-β受体激活素受体样激酶-5 （ALK5）蛋白表达降低。脑对14c -蔗糖的通透性增加，TJ蛋白（即claudin-5、occludin、zonula occluden (ZO-1)）的表达也在3 h后发生改变。选择性抑制剂SB431542对ALK5的药理抑制进一步增强了脑对14c -蔗糖的摄取，增加了TJ蛋白的表达（如claudin-3、claudin-5、occludin、ZO-1），降低了TGF-β/ALK5信号分子（如Smad2、Smad3）的核表达，提示TGF-β/ALK5信号通路在血脑屏障完整性的调节中起作用。有趣的是，在CIP前施用外源性TGF-β1激活TGF-β/ALK5通路，降低血脑屏障对14c -蔗糖的通透性。综上所述，我们的数据表明TGF-β/ALK5信号在一定程度上参与了血脑屏障功能完整性的调节。
Our laboratory has shown that peripheral inflammatory pain induced by λ-carrageenan (CIP) can increase blood–brain barrier (BBB) permeability and alter tight junction (TJ) protein expression leading to changes in BBB functional integrity. However, the intracellular signaling mechanisms involved in this pathophysiologic response have not been elucidated. Transforming growth factor (TGF)-β signaling pathways are known to regulate vascular integrity and permeability. Therefore, we examined the function of TGF-β signaling at the BBB in rats subjected to CIP. During CIP, serum TGF-β1 and protein expression of the TGF-β receptor activin receptor-like kinase-5 (ALK5) were reduced. Brain permeability to 14C-sucrose was increased and expression of TJ proteins (i.e., claudin-5, occludin, zonula occluden (ZO-1)) were also altered after 3 h CIP. Pharmacological inhibition of ALK5 with the selective inhibitor SB431542 further enhanced brain uptake of 14C-sucrose, increased TJ protein expression (i.e., claudin-3, claudin-5, occludin, ZO-1), and decreased nuclear expression of TGF-β/ALK5 signaling molecules (i.e., Smad2, Smad3), which suggests a role for TGF-β/ALK5 signaling in the regulation of BBB integrity. Interestingly, administration of exogenous TGF-β1 before CIP activated the TGF-β/ALK5 pathway and reduced BBB permeability to 14C-sucrose. Taken together, our data show that TGF-β/ALK5 signaling is, in part, involved in the regulation of BBB functional integrity.
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三个紧密连接相关的Maguks ZO-1，ZO-2和ZO-3与Claudins的Cooh Termini直接结合。
DOI：
10.1083/jcb.147.6.1351
发表时间：
1999-12-13
期刊：
The Journal of cell biology
影响因子：
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发表时间：
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