Mechanism of tolerance to tumor necrosis factor (tnf): receptor
-specific pathway and selectivity.
Takahashi, Nozomi, Peter Brouckaert, and Walter Fiers.
Laboratory of Molecular Biology, Gent University, K.L.
Ledeganckstraat 35, 9000 Gent, Belgium
APStracts 2:0069R, 1995.
Repetitive administration of low doses of tumor necrosis factor (TNF)
induces a selective tolerance to some, but not all of its effects.
The aim of the present study was to define the pathways involved in
tolerance. We observed that the induction of tolerance is mediated by
TNF-R55 triggering. TNF-R75 triggering or the addition of sensitizers
can interfere with this induction, but does not break an acquired
tolerance, as tolerant animals were also tolerant to otherwise lethal
challenges with the combination of human TNF and the sensitizers
interleukin-1 or RU38486. We further defined the selectivity of the
tolerance by examining changes in quantitative parameters such as
interleukin-6 induction, hypothermia and hemoconcentration. The
differences observed between tolerant and nontolerant animals
mimicked those observed after administration of human TNF vs. murine
TNF and were to be found in the duration rather than in the amplitude
of the induced changes. We conclude that tolerance selectively blocks
the TNF-R75-mediated pathway, especially the part mimicked by
interleukin-1 and RU38486; this pathway normally leads to a state of
unresponsiveness to glucocorticoids.
Received 5 July 1994; accepted in final form 28 February 1995.
APS Manuscript Number R359-4.
Article publication pending Am. J. Physiol. (Regulatory Integrative
Comp. Physiology).
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 21 March 1995.