Control of Cachectin (Tumor Necrosis Factor) Synthesis: Mechanisms of Endotoxin Resistance

TLDR

Cachectin (TNF) is a macrophage hormone central to endotoxin‑induced shock, and the development of a specific mRNA probe and antibody now permits detailed study of its gene regulation. In mice, peritoneal macrophages contain cachectin mRNA that is not translated into protein unless stimulated by endotoxin, which induces both mRNA synthesis and secretion, but C3H/HeJ macrophages exhibit a dual defect—reduced mRNA induction at low endotoxin levels and a post‑transcriptional block—while dexamethasone similarly suppresses cachectin production, revealing mechanisms underlying the C3H/HeJ mutation and glucocorticoid‑mediated inflammation suppression.

Abstract

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, a 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.