Department of Anesthesiology and Pain Medicine, Chonnam National University Medical School, Gwangju, South Korea.
Department of Anesthesiology and Pain Medicine, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Gwangju, South Korea.
Eur J Pharmacol. 2019 Jun 5;852:125-133. doi: 10.1016/j.ejphar.2019.02.038. Epub 2019 Feb 21.
Stearoyl lysophosphatidylcholine (sLPC) has protective effects against several lethal sepsis models, even after induction of sepsis, which is associated with sLPC-mediated inhibition of high mobility group box 1 (HMGB1) release. This study investigated the mechanism by which sLPC inhibits lipopolysaccharide (LPS)-induced extracellular secretion of HMGB1 after the onset of sepsis. sLPC increased AMPK phosphorylation and the binding of AMPK to calcium/calmodulin-dependent protein kinase kinase β (CaMKKβ), one of the upstream signals of AMPK. Inhibition of CaMKKβ activity decreased sLPC-mediated inhibition of HMGB1 release, and sLPC increased the concentration of intracellular calcium. Blocking of the macrophage G protein-coupled receptor G2A (G2A) suppressed AMPK phosphorylation, suppressed increases in the intracellular levels of calcium, and prevented the inhibition of HMGB1 release by sLPC. In particular, when macrophages were incubated with sLPC even after LPS treatment, sLPC increased the phosphorylation of AMPK and the binding of CaMKKβ and AMPK, and suppressed the secretion of HMGB1. In addition, sLPC administered 1 h before or 4 h after establishment of sepsis significantly diminished circulating HMGB1 levels in mice. sLPC inhibited LPS-induced extracellular release of HMGB1 through the activation of the G2A/calcium/CaMKKβ/AMPK pathway. These findings suggest that sLPC may be a potential anti-inflammatory agent for acute inflammatory conditions such as sepsis.
溶血磷脂酰胆碱（sLPC）对几种致死性脓毒症模型具有保护作用，甚至在脓毒症发生后也具有保护作用，这与 sLPC 介导的高迁移率族蛋白 1（HMGB1）释放抑制有关。本研究探讨了 sLPC 在脓毒症发生后抑制脂多糖（LPS）诱导的 HMGB1 细胞外分泌的机制。sLPC 增加了 AMPK 的磷酸化和 AMPK 与钙/钙调蛋白依赖性蛋白激酶激酶 β（CaMKKβ）的结合，后者是 AMPK 的上游信号之一。CaMKKβ 活性的抑制降低了 sLPC 介导的 HMGB1 释放的抑制作用，并且 sLPC 增加了细胞内钙的浓度。阻断巨噬细胞 G 蛋白偶联受体 G2A（G2A）抑制了 AMPK 的磷酸化，抑制了细胞内钙水平的增加，并防止了 sLPC 对 HMGB1 释放的抑制作用。特别是，当巨噬细胞在用 LPS 处理后甚至在用 sLPC 孵育时，sLPC 增加了 AMPK 的磷酸化和 CaMKKβ 和 AMPK 的结合，并抑制了 HMGB1 的分泌。此外，在脓毒症建立前 1 小时或建立后 4 小时给予 sLPC 可显著降低小鼠循环中 HMGB1 的水平。sLPC 通过激活 G2A/钙/CaMKKβ/AMPK 通路抑制 LPS 诱导的 HMGB1 细胞外释放。这些发现表明，sLPC 可能是脓毒症等急性炎症状态的潜在抗炎药物。
