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 of mRNA 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 mRNA accumulation, but strongly impedes translational derepression. Combined application of dexamethasone and pentoxifylline to macrophages causes a greater suppression of cachectin/TNF biosynthesis that 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.
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1 July 1990
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July 01 1990
Dexamethasone and pentoxifylline inhibit endotoxin-induced cachectin/tumor necrosis factor synthesis at separate points in the signaling pathway.
J Han,
J Han
Howard Hughes Medical Institute, University of Texas, Southwestern Medical Center, Dallas 75235.
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P Thompson,
P Thompson
Howard Hughes Medical Institute, University of Texas, Southwestern Medical Center, Dallas 75235.
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B Beutler
B Beutler
Howard Hughes Medical Institute, University of Texas, Southwestern Medical Center, Dallas 75235.
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J Han
Howard Hughes Medical Institute, University of Texas, Southwestern Medical Center, Dallas 75235.
P Thompson
Howard Hughes Medical Institute, University of Texas, Southwestern Medical Center, Dallas 75235.
B Beutler
Howard Hughes Medical Institute, University of Texas, Southwestern Medical Center, Dallas 75235.
Online ISSN: 1540-9538
Print ISSN: 0022-1007
J Exp Med (1990) 172 (1): 391–394.
Citation
J Han, P Thompson, B Beutler; Dexamethasone and pentoxifylline inhibit endotoxin-induced cachectin/tumor necrosis factor synthesis at separate points in the signaling pathway.. J Exp Med 1 July 1990; 172 (1): 391–394. doi: https://doi.org/10.1084/jem.172.1.391
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