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J Biol Chem, Vol. 273, Issue 25, 15494-15500, June 19, 1998
B by Inducing the Processing of p105
From the Department of Biochemistry, Trinity College,
Dublin 2, Ireland
The role of ceramide as a second messenger in
tumor necrosis factor (TNF)-mediated signal transduction has been much
debated. It is supported by recent reports describing an expanding
number of potential targets for this lipid, but is opposed by those
describing how ceramide is not necessary for many TNF-mediated cellular
events. In this paper, we directly compare the effects of the
cell-permeable ceramide analogue, N-acetylsphingosine
(C2-ceramide), with TNF, on NF
B function, a
transcription factor whose activation is central to many TNF-mediated
effects. We describe how C2-ceramide failed to drive
B-linked chloramphenicol acetyltransferase gene expression in either
HL60 promyelocytic or Jurkat T lymphoma cells. Furthermore, it had no
effect on TNF-mediated transcription of this reporter gene. However,
electrophoretic mobility shift analysis following cell stimulation with
this ceramide analogue revealed a dose-responsive activation of NFB,
which was not apparent following cell treatment with the inactive
dihydro form. Activated complexes from treated cells were shown to
contain predominantly the p50 subunit, in contrast to complexes from
TNF-treated cells, where both p50 and p65/RelA subunits were present.
The specific activation of p50 homodimeric complexes by
C2-ceramide, which are known to lack trans-activating
activity, was strongly suggested from these data. Further
investigations revealed that C2-ceramide had only a
marginal effect on IB
degradation but strongly promoted the
processing of p105 to its p50 product as revealed by immunoblot
analysis. The increase in p50 arising from the processing of its p105
precursor was further established from p105/p50 ratios obtained by
scanning densitometric analysis of bands from immunoblots. TNF, on the other hand, stimulated both IB degradation and p105 processing, in accordance with previous findings. Furthermore, the effect of TNF on
NFB activation was rapid, whereas C2-ceramide required an optimal treatment time of 1 h. Interestingly, TNF was found to
increase ceramide in cells but only after a 1-h contact time. Our data
therefore suggest that ceramide promotes the activation of NFB
complexes that lack transactivating activity by enhanced processing of
p105.
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