β1-Adrenergic receptor-mediated HO-1 induction, via PI3K and p38 MAPK, by isoproterenol in RAW 264.7 cells leads to inhibition of HMGB1 release in LPS-activated RAW 264.7 cells and increases in survival rate of CLP-induced septic mice
β1-Adrenergic receptor-mediated HO-1 induction, via PI3K and p38 MAPK, by isoproterenol in RAW 264.7 cells leads to inhibition of HMGB1 release in LPS-activated RAW 264.7 cells and increases in survival rate of CLP-induced septic mice
复制标题
DOI：
10.1016/j.bcp.2011.06.041
复制
发表时间：
2011-10-01
影响因子：
5.8
通讯作者：
Chang, Ki Churl
中科院分区：
文献类型：
--
作者：
Ha, Yu Mi;Ham, Sun Ah;Chang, Ki Churl
高迁移率族蛋白B1（HMGB-1）在脓毒症相关死亡的实验研究中起重要作用。据报道，血红素加氧酶-1（HO-1）诱导剂可减少实验性脓毒症中HMGB 1的释放。以前，我们报道了β 1-肾上腺素能受体和蛋白激酶A通路在RAW 264.7细胞中异丙肾上腺素（ISO）调节HO-1表达的重要性。我们研究了ISO是否减少LPS激活的RAW 264.7细胞中HMGB 1的释放，并提高由于HO-1诱导的脓毒症小鼠的存活率。在LPS激活的RAW 264.7细胞中，ISO浓度依赖性地通过Nrf-2易位增加HO-1，并通过β（1）-肾上腺素能受体（β（1）-AR）抑制HMGB 1的释放。这一结论得到了多巴酚丁胺而不是沙丁胺醇增加两种RAW 264.7细胞中HO-1表达的发现的支持。当HO-1抑制剂ZnPPIX抑制RAW 264.7细胞中HO-1表达时，ISO不能抑制HMGB 1的释放。ISO显著抑制LPS激活的RAW 264.7细胞中I κ B-α和NF-κ B驱动的荧光素酶活性的磷酸化。此外，PI 3 K抑制剂LY 294002和p38 MAPK抑制剂SB 203580不仅能显著抑制ISO诱导HO-1的表达，还能显著抑制ISO诱导HMGB 1的释放。重要的是，ISO增加了心脏和肺组织中的HO-1蛋白表达，减少了血浆中的HMGB 1，并增加了CLP治疗的脓毒症小鼠的存活率，这一点可通过与ZnPPIX共同治疗而显著逆转。综上所述，我们得出结论，脓毒症期间通过β（1）-AR介导的HO-1诱导抑制HMGB 1释放是ISO治疗脓毒症有益作用的新机制。(C)2011 Elsevier Inc. All rights reserved.
High mobility group box (HMGB)-1 plays an important role in sepsis-associated death in experimental studies. Heme oxygenase-1 (HO-1) inducers were reported to reduce HMGB1 release in experimental sepsis. Previously, we reported on the importance of the beta 1-adrenergic receptor and protein kinase A pathway in the regulation of HO-1 expression by isoproterenol (ISO) in RAW 264.7 cells. We investigated whether ISO reduces HMGB1 release in LPS-activated RAW 264.7 cells and improves survival rate in septic mice due to HO-1 induction. ISO concentration-dependently increased HO-1 via Nrf-2 translocation and inhibited release of HMGB1 through the beta(1)-adrenergic receptor (beta(1)-AR) in LPS-activated RAW 264.7 cells. This conclusion was supported by the finding that dobutamine but not salbutamol increased HO-1 expression in both RAW 264.7 cells. ISO failed to inhibit HMGB1 release when HO-1 expression was suppressed by ZnPPIX, an HO-1 inhibitor in RAW 264.7 cells. ISO significantly inhibited phosphorylation of I kappa B-alpha and NF-kappa B-driven luciferase activity in LPS-activated RAW 264.7 cells. In addition, LY294002, a PI3K inhibitor, and SB203580, a p38 MAPK inhibitor, significantly inhibited not only HO-1 induction but also HMGB1 release by ISO. Importantly, ISO increased HO-1 protein expression in heart and lung tissues, reduced HMGB1 in plasma and increased survival rate in CLP-treated septic mice, which was significantly reversed by co-treatment with ZnPPIX. Taken together, we conclude that inhibition of HMGB1 release during sepsis via beta(1)-AR-mediated HO-1 induction is a novel mechanism for the beneficial effects of ISO in the treatment of sepsis. (C) 2011 Elsevier Inc. All rights reserved.