DeMeester S L, Buchman T G, Qiu Y, Dunnigan K, Hotchkiss R S, Karl I E, Cobb J P
Department of Surgery, Washington University, St. Louis, Missouri 63110, USA.
Shock. 1998 Jul;10(1):1-6. doi: 10.1097/00024382-199807000-00001.
Transcription factor NF-kappaB is an important regulator of the cellular response to diverse stresses. Pyrrolidine dithiocarbamate (PDTC), an inhibitor of NF-kappaB activity, was used to determine the role of this transcription factor in our model of stress-induced endothelial cell apoptosis. Porcine aortic endothelial cells were treated with an inducer of the acute phase response (LPS) followed by treatment with an inducer of the heat shock response (arsenite), a sequence that produces cell death by apoptosis. Treatment with PDTC attenuated LPS-induced NF-kappaB activity and endothelial cell death when added prior to LPS. However, PDTC unexpectedly increased cell death when given after LPS priming. This time-dependent effect of PDTC on endothelial cell death was similar to that which we had observed previously for inducers of the heat shock response. Therefore, we hypothesized that PDTC could induce the heat shock response in porcine and human endothelial cells. PDTC increased heat shock protein (HSP)-70 production and heat shock factor (HSF) activity. Thus, treatment of endothelial cells with PDTC, like other inducers of the heat shock response, increased HSP-70 levels and HSF activity and had time-dependent effects on cell death by apoptosis in primed endothelial cells. We conclude that PDTC induced the heat shock response, that induction of HSF activity may be linked with inhibition of NF-kappaB activity, and that interaction between acute phase and heat shock regulatory factors may be pivotal to determining cell fate (apoptosis).
转录因子核因子-κB是细胞对多种应激反应的重要调节因子。吡咯烷二硫代氨基甲酸盐（PDTC）是一种核因子-κB活性抑制剂，用于确定该转录因子在我们的应激诱导内皮细胞凋亡模型中的作用。用急性期反应诱导剂（脂多糖）处理猪主动脉内皮细胞，随后用热休克反应诱导剂（亚砷酸盐）处理，该序列可导致细胞凋亡死亡。在脂多糖之前添加PDTC处理可减弱脂多糖诱导的核因子-κB活性和内皮细胞死亡。然而，在脂多糖预处理后给予PDTC时，意外地增加了细胞死亡。PDTC对内皮细胞死亡的这种时间依赖性效应与我们之前观察到的热休克反应诱导剂的效应相似。因此，我们推测PDTC可在猪和人内皮细胞中诱导热休克反应。PDTC增加了热休克蛋白（HSP）-70的产生和热休克因子（HSF）的活性。因此，用PDTC处理内皮细胞，与热休克反应的其他诱导剂一样，增加了HSP-70水平和HSF活性，并对预处理内皮细胞的凋亡细胞死亡具有时间依赖性效应。我们得出结论，PDTC诱导了热休克反应，HSF活性的诱导可能与核因子-κB活性的抑制有关，急性期和热休克调节因子之间的相互作用可能对决定细胞命运（凋亡）至关重要。
