Department of Pharmacology, Chang Gung University, Kwei-San, Tao-Yuan, Taiwan.
Am J Pathol. 2010 Apr;176(4):1671-84. doi: 10.2353/ajpath.2010.090714. Epub 2010 Feb 18.
Lipoteichoic acid (LTA) plays a role in the pathogenesis of severe inflammatory responses induced by Gram-positive bacterial infection. Cytosolic phospholipase A(2) (cPLA(2)), cyclooxygenase-2 (COX-2), prostaglandin E(2) (PGE(2)), and interleukin (IL)-6 have been demonstrated to engage in airway inflammation. In this study, LTA-induced cPLA(2) and COX-2 expression and PGE(2) or IL-6 synthesis were attenuated by transfection with siRNAs of TLR2, MyD88, Akt, p42, p38, JNK2, and p65 or pretreatment with the inhibitors of PI3K (LY294002), p38 (SB202190), MEK1/2 (U0126), JNK1/2 (SP600125), and NF-kappaB (helenalin) in human tracheal smooth muscle cells (HTSMCs). LTA also induced cPLA(2) and COX-2 expression and leukocyte count in bronchoalveolar lavage fluid in mice. LTA-regulated PGE(2) or IL-6 production was inhibited by pretreatment with the inhibitors of cPLA(2) (AACOCF(3)) and COX-2 (NS-398) or transfection with cPLA(2) siRNA or COX-2 siRNA, respectively. LTA-stimulated NF-kappaB translocation or cPLA(2) phosphorylation was attenuated by pretreatment with LY294002, SB202190, U0126, or SP600125. Furthermore, LTA could stimulate TLR2, MyD88, PI3K, and Rac1 complex formation. We also demonstrated that Staphylococcus aureus could trigger these responses through a similar signaling cascade in HTSMCs. It was found that PGE(2) could directly stimulate IL-6 production in HTSMCs or leukocyte count in bronchoalveolar lavage fluid in mice. These results demonstrate that LTA-induced MAPKs activation is mediated through the TLR2/MyD88/PI3K/Rac1/Akt pathway, which in turn initiates the activation of NF-kappaB, and ultimately induces cPLA(2)/COX-2-dependent PGE(2) and IL-6 generation.
脂磷壁酸（LTA）在革兰氏阳性菌感染引起的严重炎症反应发病机制中起作用。细胞溶质磷脂酶 A2（cPLA2）、环氧化酶-2（COX-2）、前列腺素 E2（PGE2）和白细胞介素（IL）-6 已被证明参与气道炎症。在这项研究中，LTA 诱导的 cPLA2 和 COX-2 表达以及 PGE2 或 IL-6 的合成，通过转染 TLR2、MyD88、Akt、p42、p38、JNK2 和 p65 的 siRNA 或用 PI3K（LY294002）、p38（SB202190）、MEK1/2（U0126）、JNK1/2（SP600125）和 NF-kappaB（helenalin）抑制剂预处理来抑制。LTA 还诱导人气管平滑肌细胞（HTSMCs）中的 cPLA2 和 COX-2 表达和肺泡灌洗液中的白细胞计数。LTA 调节的 PGE2 或 IL-6 产生分别通过用 cPLA2（AACOCF3）和 COX-2（NS-398）抑制剂预处理或转染 cPLA2 siRNA 或 COX-2 siRNA 来抑制。LTA 刺激的 NF-kappaB 易位或 cPLA2 磷酸化通过用 LY294002、SB202190、U0126 或 SP600125 预处理来减弱。此外，LTA 可以刺激 TLR2、MyD88、PI3K 和 Rac1 复合物的形成。我们还证明金黄色葡萄球菌可以通过 HTSMCs 中的类似信号级联触发这些反应。发现 PGE2 可以直接刺激 HTSMCs 中的 IL-6 产生或刺激小鼠肺泡灌洗液中的白细胞计数。这些结果表明，LTA 诱导的 MAPKs 激活是通过 TLR2/MyD88/PI3K/Rac1/Akt 途径介导的，该途径继而引发 NF-kappaB 的激活，并最终诱导 cPLA2/COX-2 依赖性 PGE2 和 IL-6 的产生。
