Release of chromatin protein HMGB1 by necrotic cells triggers inflammation
Release of chromatin protein HMGB1 by necrotic cells triggers inflammation
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DOI：
10.1038/nature00858
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发表时间：
2002-07-11
期刊：
影响因子：
64.8
通讯作者：
Bianchi, ME
中科院分区：
文献类型：
--
作者：
Scaffidi, P;Misteli, T;Bianchi, ME
高迁移率族蛋白1（HMGB 1）是一种核因子和分泌蛋白。在细胞核中，它作为一种结构性染色质结合因子，使DNA弯曲并促进蛋白质在特定DNA靶点上的组装（1，2）。在细胞外，它以高亲和力结合至α-淀粉样蛋白（晚期糖基化终产物的受体）3，并且是炎症的有效介质（4-6）。HMGB 1由活化的单核细胞和巨噬细胞分泌（4），并由坏死或受损细胞被动释放（7-9）。在这里，我们报告说HMGB 1（-/-）坏死细胞促进炎症的能力大大降低，这证明HMGB 1的释放可以向其邻居发出细胞死亡的信号。凋亡细胞即使在经历继发性坏死和部分自溶后也不释放HMGB 1，因此即使不被吞噬细胞迅速清除，也不能促进炎症。在凋亡细胞中，由于组蛋白的普遍乙酰化不足，HMGB 1与染色质牢固结合，如果染色质脱乙酰化被阻止，则HMGB 1在细胞外介质中释放（促进炎症）。因此，经历凋亡的细胞被编程为抑制由已被创伤损伤或杀死的细胞传播的信号。
High mobility group 1 (HMGB1) protein is both a nuclear factor and a secreted protein. In the cell nucleus it acts as an architectural chromatin-binding factor that bends DNA and promotes protein assembly on specific DNA targets(1,2). Outside the cell, it binds with high affinity to RAGE (the receptor for advanced glycation end products) 3 and is a potent mediator of inflammation(4-6). HMGB1 is secreted by activated monocytes and macrophages(4), and is passively released by necrotic or damaged cells(7-9). Here we report that Hmgb1(-/-) necrotic cells have a greatly reduced ability to promote inflammation, which proves that the release of HMGB1 can signal the demise of a cell to its neighbours. Apoptotic cells do not release HMGB1 even after undergoing secondary necrosis and partial autolysis, and thus fail to promote inflammation even if not cleared promptly by phagocytic cells. In apoptotic cells, HMGB1 is bound firmly to chromatin because of generalized underacetylation of histone and is released in the extracellular medium (promoting inflammation) if chromatin deacetylation is prevented. Thus, cells undergoing apoptosis are programmed to withhold the signal that is broadcast by cells that have been damaged or killed by trauma.