Graduate School of Medical and Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
Int J Hyperthermia. 2009 Dec;25(8):668-76. doi: 10.3109/02656730903213366.
It is well known that heat shock proteins (HSPs) are induced by various stressors in order to confer protection against such stressors. Since stressor-induced tissue damage is involved in various diseases, especially gastrointestinal diseases, it has been thought that HSP-inducers are therapeutically beneficial for these diseases. Indirect lines of evidence suggest that HSPs provide a major protective mechanism against irritant-induced gastric lesions. However, no direct evidence exists to support this notion. On the other hand, inflammatory bowel disease (IBD) involves infiltration of leukocytes into intestinal tissue, resulting in intestinal damage. Pro-inflammatory cytokines and cell adhesion molecules (CAMs) play important roles in this infiltration of leukocytes. The roles of heat shock factor 1 (HSF1, a transcription factor for hsp genes) and heat shock proteins (HSPs) in development of IBD are unclear. In this paper, we reviewed our recent work on the role of HSPs in pathogenesis of gastric lesions and IBD by use of HSF1-null mice and transgenic mice expressing Hsp70.
This study provides the first genetic evidence that HSF1 and Hsp70 play a role in protecting against both irritant-induced gastric lesions and IBD-related colitis. The aggravation of irritant-induced gastric lesions in HSF1-null mice is due to their inability to up-regulate Hsp70, leading to apoptosis. On the other hand, this protective role of Hsp70 against colitis seems to involve various mechanisms, such as suppression of expression of pro-inflammatory cytokines and CAMs, and cell death.
众所周知，热休克蛋白（HSPs）是由各种应激源诱导产生的，以赋予对这些应激源的保护作用。由于应激源诱导的组织损伤涉及各种疾病，特别是胃肠道疾病，因此人们认为 HSP 诱导剂对这些疾病具有治疗益处。间接证据表明，HSP 提供了一种针对刺激性胃损伤的主要保护机制。然而，目前尚无直接证据支持这一观点。另一方面，炎症性肠病（IBD）涉及白细胞浸润肠道组织，导致肠道损伤。促炎细胞因子和细胞黏附分子（CAMs）在白细胞浸润中发挥重要作用。热休克因子 1（HSF1，hsp 基因的转录因子）和热休克蛋白（HSPs）在 IBD 发展中的作用尚不清楚。在本文中，我们通过使用 HSF1 基因敲除小鼠和表达 HSP70 的转基因小鼠，综述了 HSPs 在胃损伤和 IBD 发病机制中的作用的最新研究进展。
本研究首次提供遗传证据表明，HSF1 和 HSP70 在保护刺激性胃损伤和 IBD 相关结肠炎方面发挥作用。HSF1 基因敲除小鼠的刺激性胃损伤加重是由于其不能上调 HSP70，导致细胞凋亡。另一方面，HSP70 对结肠炎的这种保护作用似乎涉及多种机制，如抑制促炎细胞因子和 CAMs 的表达以及细胞死亡。
