Department of Pharmacology, School of Medicine, Gyeongsang National University and Institute of Health Sciences, Jinju 660-772, Republic of Korea.
Int Immunopharmacol. 2013 Nov;17(3):684-92. doi: 10.1016/j.intimp.2013.08.016. Epub 2013 Sep 9.
We investigated whether THI-28 [1-4-(hydroxyphenylethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline] inhibits release of high mobility group box 1 (HMGB1), a late phase cytokine of sepsis, in lipopolysaccharide (LPS)-stimulated RAW264.7 cells through heme oxygenase (HO)-1 induction so that it shows beneficial effects in the cecal ligation and puncture (CLP)-induced septic mouse model. Silencing of target genes (HO-1, Nrf-2) or pharmacological signal inhibitors was exploited to investigate the HO-1 induction by THI-28. The dependency of HO-1 by THI-28 on survival rate and circulating HMGB1 level was tested in CLP-induced septic mice. Results showed that a time- and concentration-dependent HO-1 induction by THI-28 was significantly reduced by transfection with siNrf2 RNA. The reduction of iNOS/NO and HMGB1 expression by THI-28 was significantly reversed by silencing HO-1 RNA or treatment with SB203580, a p38 MAPK inhibitor, or LY294002, a PI3K inhibitor in LPS-activated cells. Decreasing p-IκBα by THI-28 resulted in inhibition of NF-κB activity which was reversed by silencing HO-1 RNA in LPS-activated cells. Most importantly, increased survival and reduction of liver and kidney injury and circulating HMGB1 levels by THI-28 in CLP-mice were reversed by ZnPPIX, HO-1 inhibitor. Taken together, these findings suggest that the novel compound THI-28 induces the expression of HO-1 by activating the PI3K and p38 MAPK pathways and suppressed HMGB1 and iNOS production in LPS-treated macrophages and septic mice, which may be useful in treating organ injury due to sepsis.
我们研究了 THI-28[1-4-（羟苯基）乙基]-6,7-二羟基-1,2,3,4-四氢异喹啉]是否通过诱导血红素加氧酶（HO）-1来抑制脂多糖（LPS）刺激的 RAW264.7 细胞中高迁移率族蛋白 B1（HMGB1）的释放，作为细胞因子的晚期阶段，从而在盲肠结扎和穿刺（CLP）诱导的脓毒症小鼠模型中表现出有益的效果。通过沉默靶基因（HO-1、Nrf-2）或药理学信号抑制剂来研究 THI-28 对 HO-1 的诱导作用。THI-28 通过 CLP 诱导的脓毒症小鼠的 HO-1 诱导对存活率和循环 HMGB1 水平的依赖性进行了测试。结果表明，THI-28 对 HO-1 的诱导作用呈时间和浓度依赖性，而用 siNrf2 RNA 转染则显著降低。THI-28 对 iNOS/NO 和 HMGB1 表达的抑制作用，用 HO-1 RNA 沉默或用 p38 MAPK 抑制剂 SB203580 或 PI3K 抑制剂 LY294002 处理可明显逆转，在 LPS 激活的细胞中。THI-28 降低 p-IκBα，导致 NF-κB 活性抑制，用 LPS 激活的细胞中的 HO-1 RNA 沉默可逆转该抑制作用。最重要的是，在 CLP 小鼠中，THI-28 增加存活率，减少肝脏和肾脏损伤以及循环 HMGB1 水平的作用，可被 HO-1 抑制剂 ZnPPIX 逆转。总之，这些发现表明，新型化合物 THI-28 通过激活 PI3K 和 p38 MAPK 途径诱导 HO-1 的表达，并抑制 LPS 处理的巨噬细胞和脓毒症小鼠中 HMGB1 和 iNOS 的产生，这可能对治疗脓毒症引起的器官损伤有用。
