The effects of inflammatory cytokines on lymphatic endothelial barrier function.
The effects of inflammatory cytokines on lymphatic endothelial barrier function.
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DOI：
10.1007/s10456-013-9393-2
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发表时间：
2014-04
期刊：
影响因子：
9.8
通讯作者：
Zawieja, David C.
中科院分区：
文献类型：
--
作者：
Cromer, Walter E.;Zawieja, Scott D.;Tharakan, Binu;Childs, Ed W.;Newell, M. Karen;Zawieja, David C.
适当的淋巴功能是将液体、大分子、抗原和免疫细胞输送出间质所必需的。淋巴管内皮在调节淋巴收缩活动和淋巴运输中发挥着重要作用，但它作为淋巴和间质室之间屏障的作用尚不清楚。尽管炎症期间淋巴内皮屏障的完整性尚不明确，但长期以来，淋巴功能的改变与水肿和炎症有关。在本文中，我们评估了淋巴屏障对炎症刺激的完整性，这些炎症刺激通常与血液内皮通透性增加相关。我们利用不同炎症细胞因子和信号分子（包括 TNF-α、IL-6、IL-1β、IFN-γ 和 LPS）处理后的淋巴内皮细胞 (LEC) 单层屏障功能进行体外测定。所有治疗均发现单层屏障功能障碍指数适度增加（增加 20-60%），但 IFN-γ 除外，IFN-γ 导致增加超过 2.5 倍。除 IL-1β 和 LPS 治疗外，添加 LNAME 可以阻断或减少细胞因子诱导的屏障功能障碍，这表明一氧化氮具有调节作用。 LEC 屏障的降低与细胞间粘附和细胞内细胞骨架激活的调节有关。细胞因子治疗降低了 LEC 中 VE-钙粘蛋白的表达并增加了 β-连环蛋白的清除，而 LNAME 部分逆转了这一情况。同样，肌球蛋白轻链 20 在调节丝氨酸 19 位点的磷酸化，伴随着响应细胞因子治疗而升高的单层屏障功能障碍，也被 LNAME 应用削弱。这表明淋巴屏障在炎症过程中受到调节，并且某些炎症信号可能会导致渗透性大幅增加。
Proper lymphatic function is necessary for the transport of fluids, macromolecules, antigens and immune cells out of the interstitium. The lymphatic endothelium plays important roles in the modulation of lymphatic contractile activity and lymph transport, but it's role as a barrier between the lymph and interstitial compartments is less well understood. Alterations in lymphatic function have long been associated with edema and inflammation although the integrity of the lymphatic endothelial barrier during inflammation is not well-defined. In this paper we evaluated the integrity of the lymphatic barrier in response to inflammatory stimuli commonly associated with increased blood endothelial permeability. We utilized in vitro assays of lymphatic endothelial cell (LEC) monolayer barrier function after treatment with different inflammatory cytokines and signaling molecules including TNF-α, IL-6, IL-1β, IFN-γ and LPS. Moderate increases in an index of monolayer barrier dysfunction were noted with all treatments (20–60% increase) except IFN-γ which caused a greater than 2.5 fold increase. Cytokine-induced barrier dysfunction was blocked or reduced by the addition of LNAME, except for IL-1β and LPS treatments, suggesting a regulatory role for nitric oxide. The decreased LEC barrier was associated with modulation of both intercellular adhesion and intracellular cytoskeletal activation. Cytokine treatments reduced the expression of VE-cadherin and increased scavenging of β-catenin in the LECs and this was partially reversed by LNAME. Likewise the phosphorylation of myosin light chain 20 at the regulatory serine 19 site, which accompanied the elevated monolayer barrier dysfunction in response to cytokine treatment, was also blunted by LNAME application. This suggests that the lymphatic barrier is regulated during inflammation and that certain inflammatory signals may induce large increases in permeability.
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