McNamara Nancy, Gallup Marianne, Sucher Anatol, Maltseva Inna, McKemy David, Basbaum Carol
Department of Anatomy, niversity of California, San Francisco, CA 94143-0452, USA.
Am J Respir Cell Mol Biol. 2006 Jun;34(6):653-60. doi: 10.1165/rcmb.2005-0441OC. Epub 2006 Jan 26.
Bacterial flagellin can interact with both Toll-like receptor 5 (TLR5) and the cell surface glycolipid, asialoGM1, to activate an innate immune response. The induction of mucin by flagellin in human lung epithelial cells (NCIH292) is dependent on asialoGM1 ligation, ATP receptor signaling, Ca2+ mobilization, and Erk1/2 activation. Conversely, the activation of NF-kappaB by flagellin is dependent on signaling through TLR5. These results prompted us to ask whether the flagellin-induced TLR5 signaling pathway was intersecting with or mutually independent of the nucleotide receptor pathway activated downstream of asialoGM1. Herein, we demonstrate that the release of ATP induced by flagellin is dependent on a Toll signaling cascade. Although Toll was able to activate NF-kappaB in the absence of extracellular ATP, Toll required ATP to activate Erk1/2. These results suggest interdependence between the asialoGM1 and TLR5 pathways and reveal a previously unsuspected role for autocrine extracellular ATP signaling in TLR signaling.
细菌鞭毛蛋白可与Toll样受体5（TLR5）及细胞表面糖脂去唾液酸GM1相互作用，以激活先天性免疫反应。鞭毛蛋白在人肺上皮细胞（NCIH292）中诱导黏蛋白的产生依赖于去唾液酸GM1的连接、ATP受体信号传导、Ca2+动员及Erk1/2激活。相反，鞭毛蛋白对NF-κB的激活依赖于通过TLR5的信号传导。这些结果促使我们探究鞭毛蛋白诱导的TLR5信号通路是否与去唾液酸GM1下游激活的核苷酸受体通路相交或相互独立。在此，我们证明鞭毛蛋白诱导的ATP释放依赖于Toll信号级联反应。虽然在没有细胞外ATP的情况下Toll能够激活NF-κB，但Toll需要ATP来激活Erk1/2。这些结果表明去唾液酸GM1和TLR5通路之间存在相互依赖性，并揭示了自分泌细胞外ATP信号在TLR信号传导中以前未被怀疑的作用。
