Housby J N, Cahill C M, Chu B, Prevelige R, Bickford K, Stevenson M A, Calderwood S K
Dana Farber Cancer Institute and Joint Center for Radiation Therapy, Jimmy Fund Laboratories 205, Harvard Medical School, 44 Binney Street, Boston, MA 02115, USA.
Cytokine. 1999 May;11(5):347-58. doi: 10.1006/cyto.1998.0437.
Recent studies have shown that the non-steroidal anti-inflammatory drugs (NSAIDs) activate heat shock transcription factor (HSF1) from a latent cytoplasmic form to a nuclear, DNA binding state. As HSF1 can function as both an activator of heat shock genes and a repressor of non-heat shock genes such as IL1B and c- fos, we have examined the potential role of HSF1 in the effects of NSAIDs on gene expression in a human monocytic cell line THP-1. We found that two members of the NSAIDs, sodium salicylate and sulindac repress the IL1B promoter to similar degree to heat shock or HSF1 overexpression. In addition, sodium salicylate and additional NSAIDs used at concentrations that activate HSF1 also inhibited the expression of other monocytic genes (TNF-alpha, IL-1beta, IL-6, IL-8, IL-10, ICAM-1) activated by exposure to a pro-inflammatory stimulus (lipopolysaccharide, LPS). At least in the case of the IL1B promoter, repression did not seem to involve another factor whose activity is affected by the NSAIDs, NFkappaB as the IL1B promoter fragment used in our studies is not NFkappaB responsive and binds specifically to HSF1. Exposure to NSAIDs had a complex effect on HSP gene expression and while sulindac activated the stress responsive HSP70B promoter, sodium salicylate did not. In addition, only a subset of the NSAIDs induced HSP70 mRNA species. These findings reflect the properties of HSF1 which can be activated to at least two DNA binding forms only one of which activates heat shock promoters and suggest that individual NSAID family members may differentially induce one or other of these forms. Overall therefore, exposure to NSAIDs leads to a profound switch in gene expression in monocytic cells, with suppression of genes involved in macrophage activation and induction of stress genes and HSF1 appears to play a regulatory role in these effects.
近期研究表明，非甾体抗炎药（NSAIDs）可将热休克转录因子（HSF1）从潜伏的细胞质形式激活为核内DNA结合状态。由于HSF1既可以作为热休克基因的激活剂，又可以作为非热休克基因（如IL1B和c - fos）的抑制剂，我们研究了HSF1在NSAIDs对人单核细胞系THP - 1基因表达影响中的潜在作用。我们发现，NSAIDs中的水杨酸钠和舒林酸对IL1B启动子的抑制程度与热休克或HSF1过表达相似。此外，水杨酸钠和其他以激活HSF1的浓度使用的NSAIDs，也抑制了暴露于促炎刺激（脂多糖，LPS）后激活的其他单核细胞基因（TNF -α、IL - 1β、IL - 6、IL - 8、IL - 10、ICAM - 1）的表达。至少就IL1B启动子而言，抑制似乎不涉及另一个其活性受NSAIDs影响的因子NFκB，因为我们研究中使用的IL1B启动子片段对NFκB无反应，且能特异性结合HSF1。暴露于NSAIDs对热休克蛋白（HSP）基因表达有复杂影响，舒林酸激活了应激反应性HSP70B启动子，而水杨酸钠则没有。此外，只有一部分NSAIDs能诱导HSP70 mRNA种类。这些发现反映了HSF1的特性，即它可以被激活为至少两种DNA结合形式，其中只有一种能激活热休克启动子，这表明不同的NSAIDs家族成员可能会差异诱导其中一种形式。因此，总体而言，暴露于NSAIDs会导致单核细胞中基因表达发生深刻转变，抑制参与巨噬细胞激活的基因，诱导应激基因，而HSF1似乎在这些效应中发挥调节作用。
