The alarmin HMGB1 acts in synergy with endogenous and exogenous danger signals to promote inflammation
The alarmin HMGB1 acts in synergy with endogenous and exogenous danger signals to promote inflammation
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DOI：
10.1189/jlb.0908548
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发表时间：
2009-09-01
影响因子：
5.5
通讯作者：
Harris, Helena Erlandsson
中科院分区：
文献类型：
--
作者：
Hreggvidsdottir, Hulda Sigridur;Ostberg, Therese;Harris, Helena Erlandsson
核蛋白HMGB1以前已经被证明在细胞外释放时起到警报和促进炎症的作用，但是它的作用模式仍然没有很好的确定。从原核和真核来源获得高纯度的HMGB1制剂使人PBMC或滑膜成纤维细胞培养物对HMGB1单独或与辅因子结合后的激活进行了研究。HMGB1本身不能诱导可检测到的IL-6的产生。然而，当与每个单独的促炎分子，如重组人IL-1β、TLR4配体脂多糖、TLR9配体CpG-ODN或TLR1-TLR2配体Pam3CSK4相关的蛋白时，对促炎细胞因子的诱导产生强烈的促进作用。在与预先形成的HMGB1复合体共培养时，记录了生物活性，但在顺序或同时添加HMGB1和单个配体后，没有记录生物活性。HMGB1的A盒和B盒结构域具有结合内毒素和促进IL-6产生的能力。HMGB1的热变性消除了这种促进作用。与HMGB1和其他促炎分子如肿瘤坏死因子、RANKL或IL-18共培养不能诱导增强。因此，HMGB1与许多但不是所有的免疫刺激分子广泛地作用，以协同的方式放大它们的活性。J.Leukoc。比奥尔。86：655-662；2009。
The nuclear protein HMGB1 has previously been demonstrated to act as an alarmin and to promote inflammation upon extracellular release, yet its mode of action is still not well defined. Access to highly purified HMGB1 preparations from prokaryotic and eukaryotic sources enabled studies of activation of human PBMC or synovial fibroblast cultures in response to HMGB1 alone or after binding to cofactors. HMGB1 on its own could not induce detectable IL-6 production. However, strong enhancing effects on induction of proinflammatory cytokine production occurred when the protein associated with each of the separate proinflammatory molecules, rhIL-1 beta, the TLR4 ligand LPS, the TLR9 ligand CpG-ODN, or the TLR1-TLR2 ligand Pam3CSK4. The bioactivities were recorded in cocultures with preformed HMGB1 complexes but not after sequential or simultaneous addition of HMGB1 and the individual ligands. Individual A-box and B-box domains of HMGB1 had the ability to bind LPS and enhance IL-6 production. Heat denaturation of HMGB1 eliminated this enhancement. Cocultures with HMGB1 and other proinflammatory molecules such as TNF, RANKL, or IL-18 did not induce enhancement. HMGB1 thus acts broadly with many but not all immunostimulatory molecules to amplify their activity in a synergistic manner. J. Leukoc. Biol. 86: 655-662; 2009.