Department of Anesthesiology, the First Affiliated Hospital of China Medical University, 155 Nanjing Street, Heping District, Shenyang 110001, Liaoning Province, China.
The College of Clinical Medicine, China Medical University, 92 North Street, Heping District, Shenyang 110001, Liaoning Province, China.
Eur J Pharmacol. 2014 Dec 5;744:164-72. doi: 10.1016/j.ejphar.2014.10.030. Epub 2014 Oct 28.
Engagement of toll-like receptor 4 (TLR4) can activate the myeloid differentiation factor 88 (MyD88)/toll-interleukin-1-resistance domain-containing adapter-inducing interferon-β (TRIF) dependent pathways, inducing production of reactive oxygen species (ROS) in neutrophils. Propofol (PPF) has both anti-oxidant and anti-inflammatory properties. However, the molecular mechanism by which PPF influences human neutrophil function is yet to be elucidated. This study aimed to investigate the influence of PPF on lipopolysaccharide (LPS)-induced reactive oxygen species production in human neutrophils. We isolated neutrophils from the peripheral blood of 10 healthy male donors. Neither 1 µg/ml LPS nor 10-150 μmol/L PPF influenced the rate of neutrophil apoptosis, but PPF significantly inhibited LPS-mediated reactive oxygen species production in a dose-dependent manner. PPF inhibited LPS-induced expression of MyD88, tumor necrosis factor receptor-associated factor 6, and TRIF, but not the expression of interferon regulatory factor 3 or phosphorylation of p47(phox), p38-mitogen-activated protein kinase, and nuclear factor (NF)-κB, particularly in the neutrophils in which MyD88 or TRIF had been silenced by siRNA. The inhibitory effect of PPF on LPS-induced activation of p47(phox), p38-mitogen-activated protein kinase, and NF-κB was partially antagonized by over-expression of MyD88 or TRIF in neutrophils. These observations provide insights into the mechanisms responsible for the anti-inflammatory properties of PPF. PPF reduces LPS-induced production of reactive oxygen species in neutrophils via inhibiting expression of MyD88 and TRIF signaling.
Toll 样受体 4（TLR4）的激活可以激活髓样分化因子 88（MyD88）/Toll-白细胞介素-1 抵抗域包含衔接诱导干扰素-β（TRIF）依赖性途径，诱导中性粒细胞中活性氧物质（ROS）的产生。异丙酚（PPF）具有抗氧化和抗炎作用。然而，PPF 影响人中性粒细胞功能的分子机制尚未阐明。本研究旨在探讨 PPF 对人中性粒细胞脂多糖（LPS）诱导的活性氧物质产生的影响。我们从 10 名健康男性供体的外周血中分离中性粒细胞。1μg/ml LPS 或 10-150μmol/L PPF 均不影响中性粒细胞凋亡率，但 PPF 可显著抑制 LPS 介导的活性氧物质产生，呈剂量依赖性。PPF 抑制 LPS 诱导的 MyD88、肿瘤坏死因子受体相关因子 6 和 TRIF 的表达，但不抑制干扰素调节因子 3 或 p47(phox)、p38-丝裂原活化蛋白激酶和核因子（NF）-κB 的磷酸化，特别是在 MyD88 或 TRIF 被 siRNA 沉默的中性粒细胞中。PPF 对 LPS 诱导的 p47(phox)、p38-丝裂原活化蛋白激酶和 NF-κB 激活的抑制作用可被中性粒细胞中 MyD88 或 TRIF 的过表达部分拮抗。这些观察结果为 PPF 的抗炎特性提供了机制上的见解。PPF 通过抑制 MyD88 和 TRIF 信号通路的表达，减少 LPS 诱导的中性粒细胞中活性氧物质的产生。
