Department of Oral Disease Research, National Center for Geriatrics and Gerontology, Obu, Aichi, Japan.
Shock. 2011 Nov;36(5):494-500. doi: 10.1097/SHK.0b013e31822f7e58.
High-mobility group box 1 (HMGB1) is a nuclear factor and a secreted protein. During inflammation, HMGB1 is secreted into the extracellular space where it can interact with the receptor for advanced glycation end products and trigger proinflammatory signals. Extracellular HMGB1 plays a critical role in several inflammatory diseases such as sepsis and rheumatoid arthritis. Valproic acid (VPA) is one of the most frequently prescribed antiepileptic drugs. The present study was undertaken to investigate the effect of VPA on secretion of HMGB1 in systemic inflammatory responses induced by lipopolysaccharide. Pretreatment with VPA increased the susceptibility of mice to lipopolysaccharide in endotoxemia. Valproic acid induced HMGB1 release and nuclear factor κB activation in RAW-blue cells. Valproic acid promoted the phosphorylation of ERK1/2 but not that of p38 or JNK. The MEK1/2 inhibitor PD98059 also suppressed HMGB1 release and activation of nuclear factor κB induced by VPA. Valproic acid induced expression of γ-aminobutyric acid receptors in macrophages, and picrotoxin, a γ-aminobutyric acid A receptor antagonist, inhibited the VPA-activated phosphorylation of ERK and VPA-induced HMGB1 release. These results suggest that VPA may exacerbate innate immune responses to endotoxin through enhanced release of HMGB1.
高迁移率族蛋白 B1（HMGB1）是一种核因子和分泌蛋白。在炎症过程中，HMGB1 被分泌到细胞外空间，在那里它可以与晚期糖基化终产物受体相互作用并触发促炎信号。细胞外 HMGB1 在几种炎症性疾病中起着关键作用，如败血症和类风湿关节炎。丙戊酸（VPA）是最常开的抗癫痫药物之一。本研究旨在探讨 VPA 对脂多糖诱导的全身炎症反应中 HMGB1 分泌的影响。VPA 预处理增加了小鼠对内毒素血症中脂多糖的易感性。VPA 在 RAW-blue 细胞中诱导 HMGB1 释放和核因子 κB 激活。VPA 促进 ERK1/2 的磷酸化，但不促进 p38 或 JNK 的磷酸化。MEK1/2 抑制剂 PD98059 也抑制了 VPA 诱导的 HMGB1 释放和核因子 κB 激活。VPA 在巨噬细胞中诱导γ-氨基丁酸受体的表达，而 picrotoxin，一种 γ-氨基丁酸 A 受体拮抗剂，抑制了 VPA 激活的 ERK 磷酸化和 VPA 诱导的 HMGB1 释放。这些结果表明，VPA 可能通过增强 HMGB1 的释放来加剧对内毒素的固有免疫反应。
