Extracellular HSP27 mediates angiogenesis through Toll‐like receptor 3-猫眼课题宝

DOI：

10.1096/fj.12-226977

发表时间：

2013-10

期刊：

The FASEB Journal

影响因子：

通讯作者：

中科院分区：

其他

文献类型：

作者：

D. Thuringer;G. Jego;G. Wettstein;O. Terrier;L. Cronier;Nadhir Yousfi;S. Hébrard;A. Bouchot;A. Hazoumé;Anne-Laure Joly;M. Gleave;M. Rosa-Calatrava;E. Solary;C. Garrido

热休克蛋白27(HSP27)在肿瘤细胞中表达上调，并在其微环境中释放。在这里，我们发现细胞外的HSP27在鸡绒毛膜尿囊膜上具有促血管生成作用。为了探索这一效应，我们测试了生理剂量(0.1-10μg/ml)的重组人蛋白(Rh HSP27)对单层或椭圆形生长的人微血管内皮细胞(HMEC)的影响。重组人热休克蛋白27可剂量依赖性地促进内皮细胞迁移，在5(μg/ml)时达到高峰，并在12~24 h内促进球体萌发，促进血管内皮生长因子基因转录和分泌血管内皮生长因子激活的血管内皮生长因子受体2型。所有这些作用都是由重组人热休克蛋白27与Toll样受体3(TLR3)相互作用所启动的。这种相互作用可以通过免疫沉淀检测到，但似乎不是直接的，因为我们没有通过SPR分析检测到rhHSP27和单体TLR3之间的相互作用。重组人热休克蛋白27与TLR3结合后迅速内化到胞内隔室(15-30分钟内)，这是胞内钙依赖的方式激活核因子-κB所必需的。HSP27/TLR3相互作用诱导NF-κB活化，导致血管内皮生长因子介导的细胞迁移和血管生成。这种途径为抗血管生成癌症治疗提供了替代靶点。-图林格，D.，杰戈，G.，Wettstein，G.，Terrier，O.，Cronier，L.，Yousfi，N.，Hébrard，S.，Bouchot，A.，Hazoumé，A.，Joly，A-L.，Gleve，M.，Rosa-Calatrava，M.，Solary，E.，和Garrido，C.，细胞外HSP27通过Toll样受体3介导血管生成。FASE B J.27,4169-4183(2013)。Www.fasebj.org

The heat‐shock protein 27 (HSP27) is up‐regulated in tumor cells and released in their microenvironment. Here, we show that extracellular HSP27 has a proangiogenic effect evidenced on chick chorioallantoic membrane. To explore this effect, we test the recombinant human protein (rhHSP27) at physiopathological doses (0.1–10 μg/ml) onto human microvascular endothelial cells (HMECs) grown as monolayers or spheroids. When added onto HMECs, rhHSP27 dose‐dependently accelerates cell migration (with a peak at 5 (μg/ml) and favors spheroid sprouting within 12‐24 h. rhHSP27 increases VEGF gene transcription and promotes secretion of VEGF‐activating VEGF receptor type 2. Increased VEGF transcription is related to NF‐κB activation in 30 min. All of these effects are initiated by rhHSP27 interaction with Toll‐like receptor 3 (TLR3). Such an interaction can be detected by immunoprecipitation but does not seem to be direct, as we failed to detect an interaction between rhHSP27 and monomeric TLR3 by SPR analysis. rhHSP27 is rapidly internalized with a pool of TLR3 to the endosomal compartment (within 15–30 min), which is required for NF‐κB activation in a cytosolic Ca2+ ‐dependent manner. The HSP27/TLR3 interaction induces NF‐κB activation, leading to VEGF‐mediated cell migration and angiogenesis. Such a pathway provides alternative targets for antiangiogenic cancer therapy.—Thuringer, D., Jego, G., Wettstein, G., Terrier, O., Cronier, L., Yousfi, N., Hébrard, S., Bouchot, A., Hazoumé, A., Joly, A‐L., Gleave, M., Rosa‐Calatrava, M., Solary, E., and Garrido, C., Extracellular HSP27 mediates angiogenesis through Toll‐like receptor 3. FASEB J. 27, 4169–4183 (2013). www.fasebj.org

Extracellular HSP27 mediates angiogenesis through Toll‐like receptor 3

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