Endogenous signals released from necrotic cells augment inflammatory responses to bacterial endotoxin
Endogenous signals released from necrotic cells augment inflammatory responses to bacterial endotoxin
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DOI：
10.1016/j.imlet.2007.04.011
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发表时间：
2007-07-31
影响因子：
4.4
通讯作者：
Nicolls, Mark R.
中科院分区：
文献类型：
--
作者：
El Mezayen, Rabab;El Gazzar, Mohamed;Nicolls, Mark R.
经历坏死的应激细胞释放分子，作为内源性危险信号来警告和激活先天免疫细胞。HMGB I和HSP 70都在活化的单核细胞/巨噬细胞中被诱导，并且也从应激或损伤的细胞中释放。我们研究了从坏死的单核细胞/巨噬细胞释放的HMGB 1和HSP 70是否可以作为危险信号介导细菌内毒素或脂多糖（LPS）的促炎细胞因子应答。我们表明，从坏死细胞中获得的细胞裂解物直接刺激人单核细胞/巨噬细胞系THP-1中的促炎细胞因子和趋化因子反应，如通过诱导TNF-α、IL-6和IL-8 mRNA表达和蛋白质产生所揭示的。在存在LPS的情况下，坏死细胞溶解产物诱导所有三种蛋白质更强烈地增加。我们发现，HMGB 1和HSP 70确实存在于坏死细胞裂解物中，并且负责显著诱导促炎细胞因子表达，因为用针对这两种蛋白质的抗体中和阻断了在将LPS刺激的细胞与坏死细胞裂解物孵育后观察到的细胞因子产生的增加。我们还发现，新鉴定的触发受体表达的髓样细胞-1（TREM-1）参与介导HMGB 1和HSP 70诱导的细胞因子的产生。用重组嵌合体阻断THP-1细胞上的TREM-I防止了细胞因子产生的增加，而同时阻断TLR 4和TREM-I完全消除了促炎反应，表明TREM-I与TLR 4协同作用以介导来自坏死细胞的这种信号的作用。此外，用TREM-1同时阻断HMGB 1或HSP 70不会进一步降低细胞因子水平，证实了TREM-1参与介导HMGB 1和HSP 70的作用.尽管HMGB 1和HSP 70与TREM- 1的相互作用诱导了IKB α和p38的表达，这两者都是炎性细胞因子表达所需的，但TREM-1的阻断不影响IKBa表达，但显著降低了p38的活化，如Western印迹分析所揭示的。总之，这些结果表明，从坏死细胞释放的HMGB 1和HSP 70作为内源性危险信号发挥作用，以增强单核细胞/巨噬细胞中的促炎反应，并且TREM-1将这些信号传递给细胞因子表达级联。这种机制可能有助于对细菌感染的炎症反应的放大和持续。(c)2007 Elsevier B. V.保留所有权利。
Stressed cells undergoing necrosis release molecules that acts as endogenous danger signals to alert and activate innate immune cells. Both HMGB I and HSP70 are induced in activated monocytes/macrophages and also are released from stressed or injured cells. We investigated whether HMGB 1 and HSP70 released from necrotic monocytes/macrophages, can act as danger signals to mediate proinflammatory cytokine responses to bacterial endotoxin or lipopolysaccharide (LPS). We show that cell lysate, obtained from necrotic cells directly stimulates the proinflammatory cytokine and chemokine responses in human monocyte/macrophage cell line, THP-1, as revealed by the induction of TNF-alpha, IL-6 and IL-8 mRNA expression and protein production. In the presence of LPS, necrotic cell lysate induced a more robust increase in all three proteins. We found that HMGB 1 and HSP70 were indeed present in the necrotic cell lysate and were responsible for the significant induction of the proinflammatory cytokine expression, as neutralization with antibodies against both proteins blocked the increase in the cytokine production seen after incubating LPS-stimulated cells with the necrotic cell lysate. We also found that the newly identified triggering receptor expressed on myeloid cells-1 (TREM-1) was involved in mediating the HMGB 1 - and HSP70-induced cytokine production. Blocking TREM-I on THP- I cells with a recombinant chimera prevented the increase in cytokine production, while simultaneous blocking of TLR4 and TREM-1 completely abolished the proinflarnmatory response, suggesting that TREM- I synergizes with TLR4 to mediate the effects of such signals from necrotic cells. In addition, blocking HMGB I or HSP70 simultaneously with TREM- I did not decrease the cytokine level further, confirming the involvement of TREM- I in mediating the effect of HMGB 1 and HSP70. Although the interaction of HMGB 1 and HSP70 with TREM- 1 induced IKB alpha and p38 expression, both of which are required for the inflammatory cytokine expression, blockade of TREM-1 did not affect IKBa expression but markedly reduced p38 activation, as revealed by Western blot analysis. Together, these results demonstrate that HMGB1 and HSP70 released from necrotic cells function as endogenous danger signals to augment the proinflammatory responses in monocytes/ruacrophage and that TREM- I relays such signals to the cytokine expression cascade. This mechanism may contribute to the amplification and persistence of the inflammatory response to bacterial infection.(c) 2007 Elsevier B.V. All rights reserved.