Department of Pharmacology, China Medical University, Taichung, Taiwan.
Biochem Pharmacol. 2010 Jun 1;79(11):1648-57. doi: 10.1016/j.bcp.2010.01.025. Epub 2010 Jan 28.
Patients with rheumatoid arthritis (RA) are at increased risk of developing infections and appear to be particularly susceptible to septic arthritis. Lipoteichoic acid (LTA), a cell wall component of Gram-positive bacteria is an amphiphilic, negatively charged glycolipid. However, the effects of LTA on human synovial fibroblasts are largely unknown. We investigated the signaling pathway involved in IL-6 production stimulated by LTA in rheumatoid arthritis synovial fibroblasts (RASF). LTA caused concentration- and time-dependent increases in IL-6 production. LTA-mediated IL-6 production was attenuated by Toll-like receptor 2 (TLR2) monoclonal antibody or siRNA. Pretreatment with PKCdelta inhibitor (rottlerin), c-Src inhibitor (PP2), AP-1 inhibitor (tanshinone IIA) and NF-kappaB inhibitor (PDTC and TPCK) also inhibited the potentiating action of LTA. However, focal adhesion kinase (FAK) mutant and siRNA did not affect LTA-mediated IL-6 production. Stimulation of cells with LTA increased the PKCdelta and c-Src phosphorylation and kinase activity. LTA increased the accumulation of p-c-Jun and p-p65 in the nucleus, as well as AP-1 and NF-kappaB luciferase activity. LTA-mediated increase of AP-1 and NF-kappaB luciferase activity was inhibited by rottlerin and PP2 or TLR2 and PKCdelta siRNA or c-Src mutant. Our results suggest that LTA-increased IL-6 production in human synovial fibroblasts via the TLR2 receptor, PKCdelta, c-Src, AP-1 and NF-kappaB signaling pathways.
类风湿关节炎（RA）患者发生感染的风险增加，且似乎特别容易发生化脓性关节炎。脂磷壁酸（LTA）是革兰氏阳性菌细胞壁的组成部分，是一种两亲性的带负电荷的糖脂。然而，LTA 对人滑膜成纤维细胞的影响在很大程度上尚不清楚。我们研究了 LTA 刺激类风湿关节炎滑膜成纤维细胞（RASF）产生 IL-6 所涉及的信号通路。LTA 引起 IL-6 产生呈浓度和时间依赖性增加。TLR2 单克隆抗体或 siRNA 可减弱 LTA 介导的 IL-6 产生。PKCδ抑制剂（rottlerin）、c-Src 抑制剂（PP2）、AP-1 抑制剂（丹参酮 IIA）和 NF-κB 抑制剂（PDTC 和 TPCK）预处理也抑制了 LTA 的增强作用。然而，粘着斑激酶（FAK）突变体和 siRNA 不影响 LTA 介导的 IL-6 产生。用 LTA 刺激细胞可增加 PKCδ和 c-Src 的磷酸化和激酶活性。LTA 增加了核内 p-c-Jun 和 p-p65 的积累，以及 AP-1 和 NF-κB 荧光素酶活性。rottlerin 和 PP2 或 TLR2 和 PKCδ siRNA 或 c-Src 突变体抑制了 LTA 介导的 AP-1 和 NF-κB 荧光素酶活性的增加。我们的结果表明，LTA 通过 TLR2 受体、PKCδ、c-Src、AP-1 和 NF-κB 信号通路增加人滑膜成纤维细胞的 IL-6 产生。
