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Blood, Vol. 93 No. 1 (January 1), 1999:
pp. 217-225
Ceramide and Cyclic Adenosine Monophosphate (cAMP) Induce cAMP
Response Element Binding Protein Phosphorylation via Distinct Signaling
Pathways While Having Opposite Effects on Myeloid Cell Survival
Michael P. Scheid,
Ian N. Foltz,
Peter R. Young,
John W. Schrader, and
Vincent Duronio
From the Department of Medicine and The Biomedical Research Centre,
University of British Columbia and Vancouver Hospital and Health
Sciences Centre, Vancouver, Canada; and SmithKline Beecham, King of
Prussia, PA.
The role of ceramide as a second messenger is a subject of great
interest, particularly since it is implicated in signaling in response
to inflammatory cytokines. Ceramide induces apoptosis in both
cytokine-dependent MC/9 cells and factor-independent U937 cells.
Elevation of cyclic adenosine monophosphate (cAMP) levels inhibits
apoptosis induced by ceramide and several other treatments. One target of cAMP-mediated signaling is the transcription factor CREB
(cAMP response element binding protein), and recently CREB phosphorylation at an activating site has been shown to also be mediated by a cascade involving p38 mitogen-activated protein kinase
(MAPK), one of the stress-activated MAP kinases. Because no role for
p38 MAPK in apoptosis has been firmly established, we examined the
relationship between p38 MAPK and CREB phosphorylation under various
conditions. Ceramide, or sphingomyelinase, like tumor necrosis
factor- (TNF-) or the hematopoietic growth factor, interleukin-3
(IL-3), was shown to activate p38 MAPK, which in turn activated MAPKAP
kinase-2. Each of these treatments led to phosphorylation of CREB (and
the related factor ATF-1). A selective p38 MAPK inhibitor,
SB203580, blocked TNF-- or ceramide-induced CREB phosphorylation,
but had no effect on the induction of apoptosis mediated by these
agents. The protective agents cAMP and IL-3 also led to CREB
phosphorylation, but this effect was independent of p38 MAPK, even
though IL-3 was shown to activate both p38 MAPK and MAPKAP kinase-2.
Therefore, the opposing effects on apoptosis observed with cAMP and
IL-3, compared with ceramide and TNF-, could not be explained on the
basis of phosphorylation of CREB. In addition, because SB203580 had no
effect of TNF- or ceramide-induced apoptosis, our results strongly
argue against a role for p38 MAPK in the induction of TNF-- or
ceramide-induced apoptosis.
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