Bacterial endotoxin stimulates macrophages to release HMGB1 partly through CD14- and TNF-dependent mechanisms
Bacterial endotoxin stimulates macrophages to release HMGB1 partly through CD14- and TNF-dependent mechanisms
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DOI：
10.1189/jlb.0404242
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发表时间：
2004-11-01
影响因子：
5.5
通讯作者：
Wang, HC
中科院分区：
文献类型：
--
作者：
Chen, GQ;Li, JH;Wang, HC
细菌内毒素[脂多糖（LPS）]刺激巨噬细胞依次释放早期[肿瘤坏死因子（TNF）]和晚期[高迁移率族蛋白B1（HMGB1）]促炎细胞因子。先前已证明内毒素诱导TNF产生需要CD14和丝裂原活化蛋白激酶[MAPK；例如，p38和细胞外信号调节激酶（ERK）1/2]，但对于它们在内毒素介导的HMGB1释放中的作用知之甚少。在此，我们证明在原代小鼠腹腔巨噬细胞培养物中，CD14表达的基因缺失消除了LPS诱导的TNF产生，但仅部分减弱了LPS诱导的HMGB1释放。用特异性抑制剂（SB203580、SB202190、U0126或PD98059）对p38或ERK1/2 MAPK进行药理学抑制显著减弱了LPS诱导的TNF产生，但未能抑制LPS诱导的HMGB1释放。同样，一种内源性免疫抑制分子——精胺，未能抑制LPS诱导的p38 MAPK活化，但仍显著减弱了LPS介导的HMGB1释放。用中和抗体直接抑制TNF活性或TNF表达的基因缺失部分减弱了低浓度（例如，10 ng/ml）LPS诱导的巨噬细胞HMGB1释放。综上所述，这些数据表明LPS刺激巨噬细胞释放HMGB1部分是通过CD14和TNF依赖的机制。
Bacterial endotoxin [lipopolysaccharide (LPS)] stimulates macrophages to sequentially release early [tumor necrosis factor (TNF)] and late [high mobility group box 1 (HMGB1)] proinflammatory cytokines. The requirement of CD14 and mitogen-activated protein kinases [MAPK; e.g., p38 and extracellular signal-regulated kinase (ERK)1/2] for endotoxin-induced TNF production has been demonstrated previously, but little is known about their involvement in endotoxin-mediated HMGB1 release. Here, we demonstrated that genetic disruption of CD14 expression abrogated LPS-induced TNF production but only partially attenuated LPS-induced HMGB1 release in cultures of primary murine peritoneal macrophages. Pharmacological suppression of p38 or ERK1/2 MAPK with specific inhibitors (SB203580, SB202190, U0126, or PD98059) significantly attenuated LPS-induced TNF production hut failed to inhibit LPS-induced HMGB1 release. Consistently, an endogenous, immunosuppressive molecule, spermine, failed to inhibit LPS-induced activation of p38 MAPK and yet, still significantly attenuated LPS-mediated HMGB1 release. Direct suppression of TNF activity with neutralizing antibodies or genetic disruption of TNF expression partially attenuated HMGB1 release from macrophages induced by LPS at lower concentrations (e.g., 10 ng/ml). Taken together, these data suggest that LPS stimulates macrophages to release HMGB1 partly through CD14- and TNF-dependent mechanisms.