Dexamethasone and pentoxifylline inhibit endotoxin-induced cachectin/tumor necrosis factor synthesis at separate points in the signaling pathway

J. Han, P. Thompson, B. Beutler

Research output: Contribution to journalArticle

488 Scopus citations

Abstract

The induction of cachectin/tumor necrosis factor (TNF) synthesis by bacterial endotoxins is a process that entails activation at several levels. Cachectin/TNF gene transcription is accelerated, leading to rapid accumulation ofmP NA within the macrophage cytosol. In addition, translational derepression occurs, leading to far more efficient message utilization. Through the use of posttranscriptional reporter constructs, we now demonstrate that certain agents capable of inhibiting cachectin/TNF biosynthesis operate through different mechanisms. In RAW 264.7 macrophages, pentoxifylline blocks cachectin/TNF mRNA accumulation but has no effect upon the efficiency of reporter mRNA translation. Dexamethasone, on the other hand, has only a modest effect on cachectin/TNF mkNA accumulation, but strongly impedes translational derepression. Combined application of dexamethasone and pentoxifylline to macrophages causes a greater suppression of cachectin/TNF biosynthesis than can be achieved by either agent alone. These findings suggest that the signaling pathway activated by endotoxin is branched, and that selective inhibition of different parts of the pathway may be achieved through the use of distinct agents.

Original languageEnglish (US)
Pages (from-to)391-394
Number of pages4
JournalJournal of Experimental Medicine
Volume172
Issue number1
DOIs
StatePublished - Jul 1 1990

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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