Valproic acid increases susceptibility to endotoxin shock through enhanced release of HMGB1
Valproic acid increases susceptibility to endotoxin shock through enhanced release of HMGB1
复制标题
丙戊酸通过增强 HMGB1 的释放而增加对内毒素休克的敏感性
DOI：
10.1097/shk.0b013e31822f7e58
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发表时间：
2011
期刊：
影响因子：
3.1
通讯作者：
et al
中科院分区：
文献类型：
--
作者：
Sugiura;et al
高迁移率族蛋白1（HMGB 1）是一种核因子和分泌蛋白。在炎症过程中，HMGB 1被分泌到细胞外空间，在那里它可以与晚期糖基化终产物的受体相互作用并触发促炎信号。细胞外HMGB 1在多种炎症性疾病如败血症和类风湿性关节炎中起关键作用。丙戊酸（VPA）是最常用的抗癫痫药物之一。本研究旨在探讨VPA对脂多糖诱导的全身炎症反应中HMGB 1分泌的影响。VPA预处理可增加内毒素血症小鼠对脂多糖的易感性。丙戊酸诱导RAW-蓝细胞中HMGB 1释放和核因子κB活化。丙戊酸促进ERK 1/2的磷酸化，但不促进p38或JNK的磷酸化。MEK 1/2抑制剂PD 98059也抑制VPA诱导的HMGB 1释放和核因子κB活化。丙戊酸可诱导巨噬细胞γ-氨基丁酸受体的表达，γ-氨基丁酸A受体拮抗剂印防己毒素可抑制VPA激活的ERK磷酸化和VPA诱导的HMGB 1释放。这些结果表明，VPA可能通过增强HMGB 1的释放而加剧对内毒素的先天免疫应答。
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.