Sa. Barber et al., STIMULATION OF THE CERAMIDE PATHWAY PARTIALLY MIMICS LIPOPOLYSACCHARIDE-INDUCED RESPONSES IN MURINE PERITONEAL-MACROPHAGES, Infection and immunity, 64(8), 1996, pp. 3397-3400
Recent studies have suggested that lipopolysaccharide (LIPS) stimulate
s cells by mimicking the second-messenger function of ceramide, a lipi
d generated in the cell by the action of sphingomyelinase (SMase), To
examine this possibility further, we compared the abilities of LPS, SM
ase, and/or ceramide analogs to induce cytokine secretion, modulate ge
ne expression, and induce endotoxin tolerance in macrophages, SMase an
d LPS induced secretion of tumor necrosis factor alpha (TNF-alpha) to
comparable degrees; however, unlike LPS, SMase failed to stimulate det
ectable interferon activity, Cell-permeable analogs of ceramide induce
d the expression of many LPS-inducible genes; however, the expression
of interferon-inducible protein 10 (IP-10) and interferon consensus se
quence-binding protein (ICSBP) mRNAs was significantly lower than that
induced by LPS. Both SMase-induced TNF-alpha secretion and LPS-induce
d TNF-alpha secretion were inhibited by pretreatment with a serine/thr
eonine phosphatase inhibitor, calyculin A. Macrophages preexposed in v
itro to LPS to induce a well-characterized state of endotoxin toleranc
e secreted little or no TNF-alpha upon secondary challenge with either
LPS or SMase, whereas macrophages preexposed to SMase secreted high l
evels of TNF-alpha upon secondary stimulation with LPS or SMase, Colle
ctively, these results suggest that ceramide activates a subset of LPS
-induced signaling pathways in murine peritoneal exudate macrophages.