Davé Shaival H, Tilstra Jeremy S, Matsuoka Katsuyoshi, Li Fengling, DeMarco Richard A, Beer-Stolz Donna, Sepulveda Antonia R, Fink Mitchell P, Lotze Michael T, Plevy Scott E
Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
J Leukoc Biol. 2009 Sep;86(3):633-43. doi: 10.1189/jlb.1008662. Epub 2009 May 19.
Signals from stressed cells and the enteric microbiota activate macrophages and dendritic cells and mediate intestinal inflammation. HMGB1 serves as an immunogenic stimuli causing release of inflammatory cytokines by myeloid cells. Ethyl pyruvate inhibits secretion of HMGB1 and improves survival in models of endotoxemia and hemorrhagic shock. We reasoned that ethyl pyruvate may be protective in colitis, which involves similar inflammatory pathways. In IL-10(-/-) mice with established chronic colitis, ethyl pyruvate administration ameliorated colitis and reduced intestinal cytokine production. IL-10(-/-) mice demonstrated increased intestinal HMGB1 expression and decreased expression of RAGE compared with wild-type mice. Fecal HMGB1 levels were decreased in ethyl pyruvate-treated mice. Furthermore, ethyl pyruvate induced HO-1 expression in intestinal tissue. In TNBS-induced colitis, intrarectal administration of ethyl pyruvate resulted in amelioration of colitis and reduced intestinal cytokine production. In LPS-activated murine macrophages, ethyl pyruvate decreased expression of IL-12 p40 and NO production but did not affect IL-10 levels. Ethyl pyruvate did not inhibit nuclear translocation of NF-kappaB family members but attenuated NF-kappaB DNA binding. Additionally, ethyl pyruvate induced HO-1 mRNA and protein expression and HO-1 promoter activation. Moreover, ethyl pyruvate prevented nuclear-to-cytoplasmic translocation of HMGB1. In conclusion, the HMGB1/RAGE pathway has pathophysiologic and diagnostic significance in experimental colitis. Ethyl pyruvate and other strategies to inhibit HMGB1 release and function represent promising interventions in chronic inflammatory diseases.
来自应激细胞和肠道微生物群的信号激活巨噬细胞和树突状细胞，并介导肠道炎症。高迁移率族蛋白B1（HMGB1）作为一种免疫原性刺激物，可导致髓样细胞释放炎性细胞因子。丙酮酸乙酯可抑制HMGB1的分泌，并提高内毒素血症和失血性休克模型中的生存率。我们推测丙酮酸乙酯可能对结肠炎具有保护作用，因为结肠炎涉及类似的炎症途径。在已建立慢性结肠炎的白细胞介素10基因敲除（IL-10(-/-)）小鼠中，给予丙酮酸乙酯可改善结肠炎并减少肠道细胞因子的产生。与野生型小鼠相比，IL-10(-/-)小鼠的肠道HMGB1表达增加，而晚期糖基化终末产物受体（RAGE）表达降低。经丙酮酸乙酯处理的小鼠粪便中HMGB1水平降低。此外，丙酮酸乙酯可诱导肠道组织中血红素氧合酶-1（HO-1）的表达。在三硝基苯磺酸（TNBS）诱导的结肠炎中，经直肠给予丙酮酸乙酯可改善结肠炎并减少肠道细胞因子的产生。在脂多糖（LPS）激活的小鼠巨噬细胞中，丙酮酸乙酯可降低白细胞介素12 p40的表达和一氧化氮（NO）的产生，但不影响白细胞介素10水平。丙酮酸乙酯不抑制核因子κB（NF-κB）家族成员的核转位，但可减弱NF-κB与DNA的结合。此外，丙酮酸乙酯可诱导HO-1 mRNA和蛋白表达以及HO-1启动子激活。此外，丙酮酸乙酯可阻止HMGB1从细胞核向细胞质的转位。总之，HMGB1/RAGE途径在实验性结肠炎中具有病理生理学和诊断意义。丙酮酸乙酯及其他抑制HMGB1释放和功能的策略是慢性炎症性疾病中有前景的干预措施。
