Immunomodulatory Drugs Regulate HMGB1 Release from Activated Human Monocytes
Immunomodulatory Drugs Regulate HMGB1 Release from Activated Human Monocytes
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DOI：
10.2119/molmed.2010.00031
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发表时间：
2010-09-01
影响因子：
5.7
通讯作者：
Harris, Helena Erlandsson
中科院分区：
文献类型：
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作者：
Schierbeck, Hanna;Wahamaa, Heidi;Harris, Helena Erlandsson
几种HMGB1特异性拮抗剂已经在包括关节炎在内的多种炎症性疾病临床前试验模型中提供了有益的结果。由于尚未有针对HMGB1的靶向治疗进入临床，我们进行了体外研究，以调查是否有任何一种成熟的抗风湿药物抑制HMGB1释放，作为其作用模式的一部分。新鲜纯化的健康供者外周血单核细胞在脂多糖和干扰素伽马的培养中被刺激，导致ELISPOT检测到HMGB1和肿瘤坏死因子的释放。用地塞米松、可的松、氯喹、硫代马酸金钠、甲氨蝶呤、秋水仙碱、依那西普或阿纳金钠等药物相关剂量的地塞米松、硫代马酸金钠和氯喹以剂量依赖方式抑制HMGB1的细胞外释放。免疫组化显示地塞米松可引起HMGB1细胞内滞留。其他药物对单核细胞HMGB1分泌无明显影响。地塞米松、氯喹和依那西普在一定程度上可抑制单核细胞产生的肿瘤坏死因子。我们得出结论，地塞米松、硫代马酸金钠和氯喹具有抑制激活的单核细胞释放HMGB1的能力(C)2010范斯坦医学研究所，www.festeinInstitute te.org
Several HMGB1-specific antagonists have provided beneficial results in multiple models of inflammatory disease-preclinical trials including arthritis. Since no HMGB1-specific targeted therapy has yet reached the clinic, we have performed in vitro studies to investigate whether any of a selection of well-established antirheumatic drugs inhibit HMGB1 release as part of its mode of action Freshly purified peripheral blood monocytes from healthy donors were stimulated in cultures with LPS and IFN gamma to cause HMGB1 and TNF release detected in ELISPOT assays. Effects on the secretion were assessed in cultures supplemented with dexamethasone, cortisone, chloroquine, gold sodium thiomalate, methotrexate, colchicine, etanercept or anakinra Pharmacologically relevant doses of dexamethasone, gold sodium thiomalate and chloroquine inhibited the extracellular release of HMGB1 in a dose-dependent mode. Immunostaining demonstrated that dexamethasone caused intracellular HMGB1 retention. No effects on HMGB1 secretion were observed in cultures with activated monocytes by any of the other studied agents TNF production in LPS/IFN gamma-activated monocytes was readily downregulated by dexamethasone and, to some extent, by chloroquine and etanercept. We conclude that dexamethasone, gold sodium thiomalate and chloroquine share a capacity to inhibit HMGB1 release from activated monocytes (C) 2010 The Feinstein Institute for Medical Research, www.feinsteininstitute.org