Topological Localization of Monomeric C-reactive Protein Determines Proinflammatory Endothelial Cell Responses
Topological Localization of Monomeric C-reactive Protein Determines Proinflammatory Endothelial Cell Responses
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单体 C 反应蛋白的拓扑定位决定促炎内皮细胞反应
DOI：
10.1074/jbc.m114.555318
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发表时间：
2014-05-16
影响因子：
4.8
通讯作者：
Ji, Shang-Rong
中科院分区：
文献类型：
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作者：
Li, Hai-Yun;Wang, Jing;Ji, Shang-Rong
背景：单体C反应蛋白（mCRP）可能通过诱导内皮细胞活化而参与动脉粥样硬化的形成。结果：mCRP诱导内皮细胞（EC）的反应弱得多，从基底侧比从顶面的EC。结论：组织相关的mCRP可能对EC激活贡献不大。重要性：炎症介质的局部分布是决定慢性血管炎症的重要因素，单体C反应蛋白（monomeric C-reactive protein，mCRP）激活内皮细胞（endothelial cells，ECs）参与动脉粥样硬化的形成。然而，mCRP在体外对EC的强效促炎作用似乎与mCRP在小鼠模型中的动脉粥样硬化保护作用不相容。由于mCRP主要在炎症组织内产生，并迅速从循环中清除，我们测试了这些差异是否可以通过血管内对mCRP反应的拓扑差异来解释。在Transwell培养模型中，将mCRP添加至完整人冠状动脉EC单层的顶端（管腔）而非基底外侧（管腔外）表面引起MCP-1、IL-8和IL-6的显著上调。无论EC类型或实验条件如何（例如，在滤器或细胞外基质包被表面上培养EC），均一致观察到mCRP的这种极化刺激。因此，我们检测到丰富的脂筏微区，主要的表面传感器的mCRP的EC，在顶端膜，导致优先顶端结合的mCRP和激活的EC通过极化诱导磷脂酶C，p38 MAPK，和NF-B信号通路。此外，LPS和IL-1诱导EC激活也表现出拓扑依赖性，而TNF-α没有。总之，这些结果表明，组织相关的mCRP可能对EC激活的贡献很小。因此，拓扑定位是决定mCRP和其他促炎介质对慢性血管炎症的贡献的重要但经常被忽视的因素。
Background: Monomeric C-reactive protein (mCRP) may contribute to atherogenesis by inducing endothelial activation. Results: mCRP induces much weaker endothelial cell (EC) responses from the basolateral than from the apical surfaces of ECs. Conclusion: Tissue-associated mCRP likely contributes little to EC activation. Significance: Topological localization is an important factor that defines the contribution of inflammatory mediators to chronic vascular inflammation.The activation of endothelial cells (ECs) by monomeric C-reactive protein (mCRP) has been implicated in contributing to atherogenesis. However, the potent proinflammatory actions of mCRP on ECs in vitro appear to be incompatible with the atheroprotective effects of mCRP in a mouse model. Because mCRP is primarily generated within inflamed tissues and is rapidly cleared from the circulation, we tested whether these discrepancies can be explained by topological differences in response to mCRP within blood vessels. In a Transwell culture model, the addition of mCRP to apical (luminal), but not basolateral (abluminal), surfaces of intact human coronary artery EC monolayers evoked a significant up-regulation of MCP-1, IL-8, and IL-6. Such polarized stimulation of mCRP was observed consistently regardless of EC type or experimental conditions (e.g. culture of ECs on filters or extracellular matrix-coated surfaces). Accordingly, we detected enriched lipid raft microdomains, the major surface sensors for mCRP on ECs, in apical membranes, leading to the preferential apical binding of mCRP and activation of ECs through the polarized induction of the phospholipase C, p38 MAPK, and NF-B signaling pathways. Furthermore, LPS and IL-1 induction of EC activation also exhibited topological dependence, whereas TNF- did not. Together, these results indicate that tissue-associated mCRP likely contributes little to EC activation. Hence, topological localization is an important, but often overlooked, factor that determines the contribution of mCRP and other proinflammatory mediators to chronic vascular inflammation.