Institute of Neuroscience, Université catholique de Louvain, Louvain-la-Neuve, Belgium.
Cell Biol Int. 2012;36(12):1107-13. doi: 10.1042/CBI20120081.
Toll-like receptors 2 (TLR2) and 4 (TLR4) are present in the plasma membrane of skeletal muscle cells where their functions remain incompletely resolved. They can bind various extracellular ligands, such as FSL-1, lipopolysaccharide (LPS) and/or palmitic acid (PA). We have investigated the link between PA, TLR2/4 and ribosomal S6 kinase 1 (S6K1) in C2C12 myotubes. Incubation with agonists of either TLR2 or TLR4, and with a high concentration of PA, increased S6K1 phosphorylation. Canonical upstream kinases of S6K1, protein kinase B (PKB) and mammalian target of rapamycin complex 1 (mTORC1), were regulated in the opposite way by PA, indicating that these kinases were probably not involved. By using the SB202190 inhibitor, p38 MAPK (mitogen-activated protein kinase) was found to be a key mediator of PA-induced phosphorylation of S6K1. Downregulation of either tlr2 or tlr4 gene expression by small interfering RNAs prevented the activation of both p38 MAPK and S6K1 by FSL-1, LPS or PA. Thus TLR2 and TLR4 agonists can increase the level of S6K1 phosphorylation in a p38 MAPK-dependent way in C2C12 myotubes. As PA induced the same intracellular signalling, a novel atypical pathway for PA is induced at the cellular membrane level and results in a higher phosphorylation state of S6K1.
Toll-like 受体 2（TLR2）和 4（TLR4）存在于骨骼肌细胞膜中，其功能仍不完全明确。它们可以结合各种细胞外配体，如 FSL-1、脂多糖（LPS）和/或棕榈酸（PA）。我们研究了 PA、TLR2/4 和核糖体 S6 激酶 1（S6K1）之间的联系在 C2C12 肌管中。用 TLR2 或 TLR4 的激动剂和高浓度的 PA 孵育可增加 S6K1 的磷酸化。S6K1 的经典上游激酶蛋白激酶 B（PKB）和雷帕霉素复合物 1（mTORC1）的哺乳动物靶标（mTORC1）受到 PA 的相反调节，表明这些激酶可能不参与其中。通过使用 SB202190 抑制剂，发现 p38 MAPK（丝裂原活化蛋白激酶）是 PA 诱导的 S6K1 磷酸化的关键介质。用小干扰 RNA 下调 tlr2 或 tlr4 基因表达可阻止 FSL-1、LPS 或 PA 激活 p38 MAPK 和 S6K1。因此，TLR2 和 TLR4 激动剂可以通过 p38 MAPK 依赖性方式增加 C2C12 肌管中 S6K1 的磷酸化水平。由于 PA 诱导了相同的细胞内信号，因此在细胞膜水平上诱导了一种新型非典型的 PA 途径，导致 S6K1 的磷酸化状态更高。
