Thomas S C, Ryan M A, Shanley T P, Wong H R
Division of Critical Care Medicine, Children's Hospital Medical Center, Cincinnati, Ohio 45229,
FASEB J. 1998 Oct;12(13):1371-8. doi: 10.1096/fasebj.12.13.1371.
I-kappaBalpha is an intracellular protein that functions as a primary inhibitor of the proinflammatory transcription factor NF-kappaB. Induction of the stress response with heat shock was previously demonstrated to induce I-kappaBalpha gene expression. Because the stress response can also be induced by nonthermal stimuli, we determined whether induction of the stress response with prostaglandin A1 (PGA1) would induce I-kappaBalpha gene expression. Treatment of human bronchial epithelium (BEAS-2B cells) with PGA1 induced nuclear translocation of heat shock factor 1, thus confirming that PGA1 induces the stress response in BEAS-2B cells. Induction of the stress response with PGA1 increased I-kappaBalpha mRNA expression in a time-dependent manner and increased I-kappaBalpha peptide expression. Transient transfection assays involving a human I-kappaBalpha promoter-luciferase reporter construct demonstrated that induction of the stress response with PGA1 activated the I-kappaBalpha promoter. Induction of the stress response with PGA1 and concomitant induction of I-kappaBalpha were associated with inhibition of TNF-alpha-mediated secretion of interleukin 8 and with inhibition of TNF-alpha-mediated nuclear translocation and activation of NF-kappaB. These data demonstrate that induction of the stress response, by a nonthermal stimulus, increases I-kappaBalpha gene expression by a mechanism involving activation of the I-kappaBalpha promoter. Coupled with previous data demonstrating heat shock-mediated induction of I-kappaBalpha gene expression, these data suggest that I-kappaBalpha may be considered to be one of the stress proteins. The functional consequences of stress response-mediated I-kappaBalpha gene expression may involve attenuation of cellular proinflammatory responses.
I-κBα是一种细胞内蛋白，作为促炎转录因子NF-κB的主要抑制剂发挥作用。先前已证明热休克诱导应激反应可诱导I-κBα基因表达。由于应激反应也可由非热刺激诱导，我们确定前列腺素A1（PGA1）诱导应激反应是否会诱导I-κBα基因表达。用PGA1处理人支气管上皮细胞（BEAS-2B细胞）可诱导热休克因子1的核转位，从而证实PGA1可诱导BEAS-2B细胞中的应激反应。PGA1诱导应激反应以时间依赖性方式增加I-κBα mRNA表达并增加I-κBα肽表达。涉及人I-κBα启动子-荧光素酶报告基因构建体的瞬时转染试验表明，PGA1诱导应激反应可激活I-κBα启动子。PGA1诱导应激反应并伴随I-κBα的诱导与TNF-α介导的白细胞介素8分泌的抑制以及TNF-α介导的NF-κB核转位和激活的抑制有关。这些数据表明，非热刺激诱导应激反应通过涉及激活I-κBα启动子的机制增加I-κBα基因表达。结合先前证明热休克介导I-κBα基因表达的数据，这些数据表明I-κBα可被认为是应激蛋白之一。应激反应介导的I-κBα基因表达的功能后果可能涉及细胞促炎反应的减弱。
