Control of cachectin (tumor necrosis factor) synthesis

Mechanisms of endotoxin resistance

Bruce Beutler, Nadia Krochin, Ian W. Milsark, Christina Luedke, Anthony Cerami

Research output: Contribution to journalArticle

974 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)977-980
Number of pages4
JournalScience
Volume232
Issue number4753
StatePublished - 1986

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Endotoxins
Tumor Necrosis Factor-alpha
Messenger RNA
Macrophages
Thioglycolates
Inbred C3H Mouse
DNA Probes
Gene Expression Regulation
Peritoneal Macrophages
Dexamethasone
Glucocorticoids
Shock
Proteins
Hormones
Inflammation
Mutation

ASJC Scopus subject areas

  • General

Cite this

Beutler, B., Krochin, N., Milsark, I. W., Luedke, C., & Cerami, A. (1986). Control of cachectin (tumor necrosis factor) synthesis: Mechanisms of endotoxin resistance. Science, 232(4753), 977-980.

Control of cachectin (tumor necrosis factor) synthesis : Mechanisms of endotoxin resistance. / Beutler, Bruce; Krochin, Nadia; Milsark, Ian W.; Luedke, Christina; Cerami, Anthony.

In: Science, Vol. 232, No. 4753, 1986, p. 977-980.

Research output: Contribution to journalArticle

Beutler, B, Krochin, N, Milsark, IW, Luedke, C & Cerami, A 1986, 'Control of cachectin (tumor necrosis factor) synthesis: Mechanisms of endotoxin resistance', Science, vol. 232, no. 4753, pp. 977-980.
Beutler B, Krochin N, Milsark IW, Luedke C, Cerami A. Control of cachectin (tumor necrosis factor) synthesis: Mechanisms of endotoxin resistance. Science. 1986;232(4753):977-980.
Beutler, Bruce ; Krochin, Nadia ; Milsark, Ian W. ; Luedke, Christina ; Cerami, Anthony. / Control of cachectin (tumor necrosis factor) synthesis : Mechanisms of endotoxin resistance. In: Science. 1986 ; Vol. 232, No. 4753. pp. 977-980.
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