van Dijk Irene A, Ferrando Maria Laura, van der Wijk Anne-Eva, Hoebe Ron A, Nazmi Kamran, de Jonge Wouter J, Krawczyk Przemek M, Bolscher Jan G M, Veerman Enno C I, Stap Jan
Department of Medical Biology and Core Facility Cellular Imaging, Van Leeuwenhoek Centre for Advanced Microscopy-Academic Medical Center (LCAM-AMC), University of Amsterdam, Amsterdam, The Netherlands;
Department of Oral Biochemistry, University of Amsterdam and Vrije Universiteit (VU) Amsterdam, Amsterdam, The Netherlands.
FASEB J. 2017 Sep;31(9):3922-3933. doi: 10.1096/fj.201700180R. Epub 2017 May 18.
Histatins are multifunctional histidine-rich peptides secreted by the salivary glands and exclusively present in the saliva of higher primates, where they play a fundamental role in the protection of the oral cavity. Our previously published results demonstrated that histatin-1 (Hst1) promotes cell-substrate adhesion in various cell types and hinted that it could also be involved in cell-cell adhesion, a process of fundamental importance to epithelial and endothelial barriers. Here we explore the effects of Hst1 on cellular barrier function. We show that Hst1 improved endothelial barrier integrity, decreased its permeability for large molecules, and prevented translocation of bacteria across epithelial cell layers. These effects are mediated by the adherens junction protein E-cadherin (E-cad) and by the tight junction protein zonula occludens 1, as Hst1 increases the levels of zonula occludens 1 and of active E-cad. Hst1 may also promote epithelial differentiation as Hst1 induced transcription of the epithelial cell differentiation marker apolipoprotein A-IV (a downstream E-cad target). In addition, Hst1 counteracted the effects of epithelial-mesenchymal transition inducers on the outgrowth of oral cancer cell spheroids, suggesting that Hst1 affects processes that are implicated in cancer progression.-Van Dijk, I. A., Ferrando, M. L., van der Wijk, A.-E., Hoebe, R. A., Nazmi, K., de Jonge, W. J., Krawczyk, P. M., Bolscher, J. G. M., Veerman, E. C. I., Stap, J. Human salivary peptide histatin-1 stimulates epithelial and endothelial cell adhesion and barrier function.
富组蛋白是由唾液腺分泌的多功能富含组氨酸的肽，仅存在于高等灵长类动物的唾液中，在口腔保护中发挥着重要作用。我们之前发表的结果表明，组蛋白-1（Hst1）促进多种细胞类型中的细胞-底物黏附，并暗示它也可能参与细胞-细胞黏附，这一过程对上皮和内皮屏障至关重要。在此，我们探讨Hst1对细胞屏障功能的影响。我们发现Hst1改善了内皮屏障的完整性，降低了其对大分子的通透性，并阻止细菌跨上皮细胞层移位。这些作用是由黏附连接蛋白E-钙黏蛋白（E-cad）和紧密连接蛋白闭合蛋白1介导的，因为Hst1增加了闭合蛋白1和活性E-钙黏蛋白的水平。Hst1还可能促进上皮分化，因为Hst1诱导上皮细胞分化标志物载脂蛋白A-IV（E-钙黏蛋白的下游靶点）的转录。此外，Hst1抵消了上皮-间质转化诱导剂对口腔癌细胞球体生长的影响，表明Hst1影响与癌症进展相关的过程。-范·迪克，I.A.，费兰多，M.L.，范德维克，A.-E.，霍贝，R.A.，纳兹米，K.，德容，W.J.，克拉维茨克，P.M.，博尔舍尔，J.G.M.，韦尔曼，E.C.I.，斯塔普，J.人唾液肽组蛋白-1刺激上皮和内皮细胞黏附及屏障功能。
