Beutler B, Krochin N, Milsark I W, Luedke C, Cerami A
Science. 1986 May 23;232(4753):977-80. doi: 10.1126/science.3754653.
Cachectin (tumor necrosis factor) is a macrophage hormone strongly implicated in the pathogenesis of endotoxin-induced shock. The availability of a DNA probe complementary to the cachectin messenger RNA (mRNA), as well as a specific antibody capable of recognizing the cachectin gene product, has made it possible to analyze the regulation of cachectin gene expression under a variety of conditions. Thioglycollate-elicited peritoneal macrophages obtained from mice contain a pool of cachectin mRNA that is not expressed as protein. When the cells are stimulated with endotoxin, large quantity of additional cachectin mRNA is produced, and immunoreactive cachectin is secreted. Macrophages from mice of the C3H/HeJ strain do not produce cachectin in response to endotoxin. A dual defect appears to prevent cachectin expression. First, a diminished quantity of cachectin mRNA is expressed in response to low concentrations of endotoxin. Second, a post-transcriptional defect prevents the production of cachectin protein. Macrophages from endotoxin-sensitive mice do not produce cachectin if they are first treated with dexamethasone, apparently for similar reasons. These findings give new insight into the nature of the C3H/HeJ mutation and suggest an important mechanism by which glucocorticoids may act to suppress inflammation.
恶病质素（肿瘤坏死因子）是一种巨噬细胞激素，与内毒素性休克的发病机制密切相关。与恶病质素信使核糖核酸（mRNA）互补的DNA探针以及能够识别恶病质素基因产物的特异性抗体的存在，使得在各种条件下分析恶病质素基因表达的调控成为可能。从小鼠获得的经巯基乙酸盐诱导的腹腔巨噬细胞含有一组未表达为蛋白质的恶病质素mRNA。当细胞受到内毒素刺激时，会产生大量额外的恶病质素mRNA，并分泌出具有免疫反应性的恶病质素。C3H/HeJ品系小鼠的巨噬细胞对内毒素无反应，不产生恶病质素。似乎有双重缺陷阻止恶病质素的表达。首先，低浓度内毒素刺激时，恶病质素mRNA的表达量减少。其次，转录后缺陷阻止了恶病质素蛋白的产生。如果先用地塞米松处理，来自内毒素敏感小鼠的巨噬细胞也不会产生恶病质素，原因显然类似。这些发现为C3H/HeJ突变的本质提供了新的见解，并提示了糖皮质激素可能作用于抑制炎症的重要机制。
