Genetic evidence for a protective role for heat shock factor 1 and heat shock protein 70 against colitis
Genetic evidence for a protective role for heat shock factor 1 and heat shock protein 70 against colitis
复制标题
DOI：
10.1074/jbc.m704081200
复制
发表时间：
2007-08-10
影响因子：
4.8
通讯作者：
Mizushima, Tohru
中科院分区：
文献类型：
--
作者：
Tanaka, Ken-Ichiro;Namba, Takushi;Mizushima, Tohru
炎症性肠病（IBD）涉及白细胞浸润到肠组织中，导致活性氧（ROS）诱导的肠损伤。促炎细胞因子和细胞粘附分子（CAM）在白细胞的浸润中起重要作用。热休克因子1（HSF1）和热休克蛋白（HSPs）在IBD发生发展中的作用尚不清楚。在这项研究中，我们研究了HSF1和热休克蛋白在IBD，葡聚糖硫酸钠（DSS）诱导的结肠炎动物模型中的作用。结肠炎恶化或改善，分别在HSF1基因敲除小鼠或转基因小鼠表达HSP 70（或HSF1）。DSS以HSF1依赖的方式上调结肠组织中HSP70的表达。与对照野生型小鼠相比，DSS处理的HSF1缺失小鼠或表达HSP 70的转基因小鼠中促炎细胞因子和CAM的表达以及结肠组织中观察到的细胞死亡水平分别增加或减少。相对于来自对照野生型小鼠的巨噬细胞，从HSF1缺失小鼠或表达HSP 70的转基因小鼠制备的巨噬细胞分别显示增强或降低的活性，用于响应于脂多糖刺激产生促炎细胞因子。抑制HSF1或HSP70的表达在体外刺激脂多糖诱导上调CAM或ROS诱导的细胞死亡，分别。这项研究提供了第一个遗传证据，证明HSF1和HSP 70在预防DSS诱导的结肠炎中发挥作用。此外，这种保护作用似乎涉及多种机制，如抑制促炎细胞因子和CAM的表达和ROS诱导的细胞死亡。
Inflammatory bowel disease (IBD) involves infiltration of leukocytes into intestinal tissue, resulting in intestinal damage induced by reactive oxygen species (ROS). Pro-inflammatory cytokines and cell adhesion molecules (CAMs) play important roles in this infiltration of leukocytes. The roles of heat shock factor 1 (HSF1) and heat shock proteins (HSPs) in the development of IBD are unclear. In this study, we examined the roles of HSF1 and HSPs in an animal model of IBD, dextran sulfate sodium (DSS)-induced colitis. The colitis worsened or was ameliorated in HSF1-null mice or transgenic mice expressing HSP70 (or HSF1), respectively. Administration of DSS up-regulated the expression of HSP70 in colonic tissues in an HSF1-dependent manner. Expression of pro-inflammatory cytokines and CAMs and the level of cell death observed in colonic tissues were increased or decreased in DSS-treated HSF1-null mice or transgenic mice expressing HSP70, respectively, relative to control wild-type mice. Relative to macrophages from control wildtype mice, macrophages prepared from HSF1-null mice or transgenic mice expressing HSP70 displayed enhanced or reduced activity, respectively, for the generation of pro-inflammatory cytokines in response to lipopolysaccharide stimulation. Suppression of HSF1 or HSP70 expression in vitro stimulated lipopolysaccharide induced up-regulation of CAMs or ROS-induced cell death, respectively. This study provides the first genetic evidence that HSF1 and HSP70 play a role in protecting against DSS-induced colitis. Furthermore, this protective role seems to involve various mechanisms, such as suppression of expression of pro-inflammatory cytokines and CAMs and ROS-induced cell death.