Human serum from patients with septic shock activates transcription factors STAT1, IRF1, and NF-κB and induces apoptosis in human cardiac myocytes
Human serum from patients with septic shock activates transcription factors STAT1, IRF1, and NF-κB and induces apoptosis in human cardiac myocytes
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DOI：
10.1074/jbc.m508416200
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发表时间：
2005-12-30
影响因子：
4.8
通讯作者：
Parrillo, JE
中科院分区：
文献类型：
--
作者：
Kumar, A;Kumar, A;Parrillo, JE
促炎性细胞因子与急性感染性休克患者体内心肌收缩力的抑制有关，体外模型采用暴露于此类患者血清的分离肌细胞。参与介导这种脓毒性器官功能障碍的关键途径（细胞粘附分子表达、诱导型一氧化氮合酶诱导和细胞凋亡）已知受转录因子STAT 1、IRF 1和NF-κ B调节。利用模拟人类疾病的模型，我们已经证明了暴露于人脓毒症血清的人胎儿心肌细胞中转录因子STAT 1、IRF 1和NF-κ B的激活。报告基因和电泳迁移率变动分析均表明，与人脓毒症血清孵育后，转录因子STAT 1、IRF 1和NF-κ B的活化增加了5-19倍。此外，人败血症血清诱导人胎儿心肌细胞凋亡的人胎儿心肌细胞和激活的丝裂原活化蛋白激酶c-Jun氨基末端激酶和半胱天冬酶1蛋白质印迹法测定。这些数据表明，转录因子激活和早期心肌细胞凋亡在脓毒症心肌抑制和脓毒症诱导的器官功能障碍中发挥机制作用。
Proinflammatory cytokines have been linked to depression of myocardial contractility in vivo in patients with acute septic shock and in vitro models employing isolated myocytes exposed to serum from such patients. The key pathways involved in mediating this septic organ dysfunction (cell adhesion molecule expression, inducible nitric-oxide synthase induction, and apoptosis) are known to be regulated by transcription factors STAT1, IRF1, and NF-kappa B. Utilizing a model that mimics human disease, we have demonstrated activation of the transcription factors STAT1, IRF1, and NF-kappa B in human fetal myocytes exposed to human septic serum. Both reporter and electrophoretic mobility shift assays demonstrated a 5-19-fold increase in activation of transcription factors STAT1, IRF1, and NF-kappa B in response to incubation with human septic serum. The addition of human septic serum to human fetal myocytes induced apoptosis in human fetal myocytes and activation of the mitogen-activated protein kinase c-Jun NH2-terminal kinase and caspase 1 as measured by Western blot. These data suggest that transcription factor activation and early myocyte apoptosis play a mechanistic role in septic myocardial depression and sepsis-induced organ dysfunction.