Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado, USA.
Mucosal Immunol. 2013 Sep;6(5):960-71. doi: 10.1038/mi.2012.134. Epub 2013 Jan 16.
Inflammatory bowel disease (IBD) is a chronic inflammatory condition thought to reflect a failure of the enteral immune system to adequately regulate itself. Inflammatory stress drives upregulation of heat-shock proteins (HSPs), including the pro-inflammatory chaperone, HSP90. This protein sequesters the transcription factor, heat-shock factor 1 (HSF1) in the cytoplasm preventing transcription of a number of anti-inflammatory proteins. We hypothesized that inhibition of HSP90 would exert an anti-inflammatory effect and thereby attenuate intestinal inflammation in murine models of IBD. Inhibition of HSP90 with 17-allylaminogeldanamycin (17-AAG) reduced inflammation in acute dextran sodium sulfate and chronic CD45RB(High) colitis models coinciding with increased interleukin (IL)-10 production in the colon. Regulatory T cells (Tregs) from mice treated with 17-AAG demonstrated significantly greater suppressive capacity in vitro abolished in HSF1-/- or IL-10-/- cells. Finally, Tregs treated with 17-AAG exhibited increased nuclear localization of HSF1 with resultant upregulation of HSF1 response genes, including HSP70, HSP90 and IL-10.
炎症性肠病（IBD）被认为是一种肠道免疫系统失调的慢性炎症性疾病。炎症应激会导致热休克蛋白（HSPs）的上调，包括促炎伴侣蛋白 HSP90。这种蛋白质将转录因子热休克因子 1（HSF1）隔离在细胞质中，从而阻止了许多抗炎蛋白的转录。我们假设抑制 HSP90 将发挥抗炎作用，从而减轻 IBD 小鼠模型中的肠道炎症。用 17-烯丙基氨基格尔德霉素（17-AAG）抑制 HSP90 可减少急性葡聚糖硫酸钠和慢性 CD45RB（High）结肠炎模型中的炎症，同时增加结肠中白细胞介素（IL）-10 的产生。用 17-AAG 处理的小鼠中的调节性 T 细胞（Tregs）在体外显示出显著增强的抑制能力，但在 HSF1-/-或 IL-10-/-细胞中被废除。最后，用 17-AAG 处理的 Tregs 显示 HSF1 的核定位增加，导致 HSF1 反应基因（包括 HSP70、HSP90 和 IL-10）的上调。
