Bulut Y, Faure E, Thomas L, Equils O, Arditi M
Division of Pediatric Critical Care, Ahmanson Department of Pediatrics, Steven Spielberg Pediatric Research Center, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
J Immunol. 2001 Jul 15;167(2):987-94. doi: 10.4049/jimmunol.167.2.987.
Toll-like receptor 2 (TLR2) and TLR4 play important roles in innate immune responses to various microbial agents. We have previously shown that human dermal endothelial cells (HMEC) express TLR4, but very little TLR2, and respond to LPS, but not to Mycobacterium tuberculosis 19-kDa lipoprotein, unless transfected with TLR2. Here we report that HMEC are unresponsive to several additional biologically relevant TLR2 ligands, including, phenol-soluble modulin (PSM), a complex of three small secreted polypeptides from the skin commensal Staphylococcus epidermidis, soluble tuberculosis factor (STF), and Borrelia burgdorferi outer surface protein A lipoprotein (OspA-L). Expression of TLR2 renders HMEC responsive to all these ligands. We further characterized the signaling pathway in response to STF, OspA-L, and PSM in TLR2-transfected HMEC. The TLR2 signaling pathway for NF-kappaB trans-activation shares the IL-1R signaling molecules. Dominant negative constructs of TLR2 or TLR6 inhibit the responses of STF and OspA-L as well as PSM in TLR2-transfected HMEC, supporting the concept of functional cooperation between TLR2 and TLR6 for all these TLR2 ligands. Moreover, we show that Toll-interacting protein (Tollip) coimmunoprecipitates with TLR2 and TLR4 using HEK 293 cells, and overexpression of Tollip inhibits NF-kappaB activation in response to TLR2 and TLR4 signaling. Collectively, these findings suggest that there is functional interaction between TLR2 and TLR6 in the cellular response to STF and OspA-L in addition to S. epidermidis (PSM) Ags, and that engagement of TLR2 triggers a signaling cascade, which shares the IL-1R signaling molecules, similar to the TLR4-LPS signaling cascade. Our data also suggest that Tollip may be an important constituent of both the TLR2 and TLR4 signaling pathways.
Toll样受体2（TLR2）和TLR4在对各种微生物制剂的固有免疫反应中发挥重要作用。我们之前已经表明，人真皮内皮细胞（HMEC）表达TLR4，但TLR2表达很少，并且对脂多糖（LPS）有反应，但对结核分枝杆菌19-kDa脂蛋白没有反应，除非转染TLR2。在此我们报告，HMEC对其他几种生物学相关的TLR2配体无反应，包括酚溶性调节素（PSM），一种来自皮肤共生表皮葡萄球菌的三种小分泌多肽的复合物、可溶性结核因子（STF）以及伯氏疏螺旋体外膜蛋白A脂蛋白（OspA-L）。TLR2的表达使HMEC对所有这些配体产生反应。我们进一步对转染TLR2的HMEC中对STF、OspA-L和PSM的信号通路进行了表征。NF-κB反式激活的TLR2信号通路共享IL-1R信号分子。TLR2或TLR6的显性负性构建体抑制转染TLR2的HMEC中STF和OspA-L以及PSM的反应，支持TLR2和TLR6对所有这些TLR2配体进行功能协作的概念。此外，我们表明，使用HEK 293细胞时，Toll相互作用蛋白（Tollip）与TLR2和TLR4共免疫沉淀，并且Tollip的过表达抑制对TLR2和TLR4信号的NF-κB激活。总体而言，这些发现表明，除了表皮葡萄球菌（PSM）抗原外，TLR2和TLR6在对STF和OspA-L的细胞反应中存在功能相互作用，并且TLR2的激活触发了一个信号级联反应，该反应共享IL-1R信号分子，类似于TLR4-LPS信号级联反应。我们的数据还表明，Tollip可能是TLR2和TLR4信号通路的重要组成部分。
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