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*
Department of Pharmacology, National Taiwan University College of Medicine, Taipei, Taiwan; and
Cancer Center, Veterans General Hospital, Taipei, Taiwan
The goal of this study was to elucidate whether triggering the
sphingomyelin pathway modulates LPS-initiated responses. For this
purpose we investigated the effects of
N-acetylsphingosine (C2-ceramide) on
LPS-induced production of NO and PGE2 in murine RAW 264.7
macrophages and explored the signaling pathways involved. We found that
within a range of 10–50 µM, C2-ceramide inhibited
LPS-elicited NO synthase and cyclooxygenase-2 induction accompanied by
a reduction in NO and PGE2 formation. By contrast, a
structural analog of C2-ceramide that does not elicit
functional activity, C2-dihydroceramide, did not affect the
LPS response. The nuclear translocation and DNA binding study revealed
that ceramide can inhibit LPS-induced NF-
B and AP-1 activation. The
immunocomplex kinase assay indicated that IB kinase activity
stimulated by LPS was inhibited by ceramide, which concomitantly
reduced the IB
degradation caused by LPS within 1–6 h. In
concert with the decreased cytosolic p65 protein level, LPS treatment
resulted in rapid nuclear accumulation of NF-B subunit p65 and its
association with the cAMP-responsive element binding protein. Ceramide
coaddition inhibited all the LPS responses. In addition, LPS-induced
PKC and p38 mitogen-activated protein kinase activation were overcome
by ceramide. In conclusion, we suggest that ceramide inhibition of
LPS-mediated induction of inducible NO synthase and cyclooxygenase-2 is
due to reduction of the activation of NF-B and AP-1, which might
result from ceramide’s inhibition of LPS-stimulated IB kinase, p38
mitogen-activated protein kinase, and protein kinase
C.
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