The lectin-like domain of TNF protects from listeriolysin-induced hyperpermeability in human pulmonary microvascular endothelial cells - a crucial role for protein kinase C-alpha inhibition.
The lectin-like domain of TNF protects from listeriolysin-induced hyperpermeability in human pulmonary microvascular endothelial cells - a crucial role for protein kinase C-alpha inhibition.
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DOI：
10.1016/j.vph.2009.12.010
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发表时间：
2010-05
影响因子：
4
通讯作者：
Lucas, Rudolf
中科院分区：
文献类型：
--
作者：
Xiong, Chenling;Yang, Guang;Kumar, Sanjiv;Aggarwal, Saurabh;Leustik, Martin;Snead, Connie;Hamacher, Juerg;Fischer, Bernhard;Umapathy, Nagavedi S.;Hossain, Hamid;Wendel, Albrecht;Catravas, John D.;Verin, Alexander D.;Fulton, David;Black, Stephen M.;Chakraborty, Trinad;Lucas, Rudolf
李斯特菌病可导致新生儿和免疫受损患者潜在致命的肺部并发症，其特征在于广泛的渗透性水肿。李斯特菌溶血素（LLO）是单核细胞增多性李斯特菌的主要毒力因子，在体外可诱导人肺微血管内皮细胞单层通透性增高。蛋白激酶C（PKC）α/β抑制剂GÖ 6976可完全抑制LLO的通透性增加活性，并伴随活性氧（ROS）生成、RhoA活化和肌球蛋白轻链（MLC）磷酸化的增加，表明PKC在诱导屏障功能障碍中起关键作用。TNF衍生的TIP肽模拟细胞因子的凝集素样结构域，在抑制LLO诱导的蛋白激酶C-α活化、ROS产生和MLC磷酸化以及恢复RhoA/Rac 1平衡后，在体外减弱LLO诱导的通透性过高。这些结果表明，TNF的凝集素样结构域在保护LLO诱导的肺内皮细胞高通透性中具有潜在的治疗价值。
Listeriosis can lead to potentially lethal pulmonary complications in newborns and immune compromised patients, characterized by extensive permeability edema. Listeriolysin (LLO), the main virulence factor of Listeria monocytogenes, induces a dose-dependent hyperpermeability in monolayers of human lung microvascular endothelial cells in vitro. The permeability increasing activity of LLO, which is accompanied by an increased reactive oxygen species (ROS) generation, RhoA activation and myosin light chain (MLC) phosphorylation, can be completely inhibited by the protein kinase C (PKC) α/β inhibitor GÖ6976, indicating a crucial role for PKC in the induction of barrier dysfunction. The TNF-derived TIP peptide, which mimics the lectin-like domain of the cytokine, blunts LLO-induced hyperpermeability in vitro, upon inhibiting LLO-induced protein kinase C-α activation, ROS generation and MLC phosphorylation and upon restoring the RhoA/Rac 1 balance. These results indicate that the lectin-like domain of TNF has a potential therapeutic value in protecting from LLO-induced pulmonary endothelial hyperpermeability.
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