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J Biol Chem, Vol. 273, Issue 5, 2591-2600, January 30, 1998
From the Department of Pediatrics, Medical University of South
Carolina, Charleston, South Carolina 29425
The sphingomyelin signal transduction
pathway is known to play a role in mediating the action of various
cytokines. Here we examined the possible role of the sphingomyelin
signaling pathway on lipopolysaccharide (LPS)- and cytokine-mediated
production of NO and the expression of inducible nitric-oxide synthase
(iNOS). Sphingomyelinase (SMase) treatment of astrocytes increased the cellular levels of ceramide without the induction of NO production. However, incubation of LPS or cytokine-stimulated astrocytes with SMase
or by increasing intracellular ceramide by cell-permeable ceramide
analogs (C2- or C6-ceramide) or inhibitor
of ceramidase (N-oleoyl ethanolamine) led to a time- and
dose-dependent increase in the production of NO. This
increase in NO production was accompanied by an increase in iNOS
activity, iNOS protein, and iNOS mRNA. Similar to astrocytes, SMase
or ceramide analogs also stimulated the LPS- and cytokine-mediated
expression of iNOS in the C6 glial cell line. Since
activation of NF-
B is necessary for the induction of iNOS, we
examined the effect of SMase and C2-ceramide on the activation of NF-B. Although SMase or C2-ceramide alone
was ineffective in activating NF-B, both stimulated the LPS-mediated
activation of NF-B in LPS-activated astrocytes. Inhibition of
ceramide and LPS-mediated induction of iNOS by antioxidant inhibitors
of NF-B (N-acetylcysteine and pyrrolidine
dithiocarbamate) suggest that the stimulatory effect of ceramide on the
induction of iNOS is due to the stimulation of NF-B activation and
that cellular redox plays a role in the activation of NF-B and
induction of iNOS. Inhibition of LPS-mediated as well as LPS and
ceramide-mediated induction of iNOS and activation of NF-B by
PD98059, a specific inhibitor of activation of mitogen-activated
protein (MAP) kinase kinase (MEK), and FPT inhibitor II, a selective
inhibitor of Ras farnesyl protein transferase, indicate that the
Ras-MAP kinase pathway is involved in LPS-ceramide induced activation
of NF-B and induction of iNOS, and that ceramide-mediated signaling
events probably converge into the LPS-modulated MAP kinase signaling pathway resulting in greater activation of NF-B and iNOS induction. This study illustrates a novel role of the sphingomyelin-ceramide signaling pathway in stimulating the expression of iNOS via LPS- or
cytokine-mediated activation of NF-B in astrocytes.
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