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Vol. 63, Issue 3, 512-523, March 2003
in Macrophages
National Research Laboratory (MDT) (Y.H.C., S.G.K.), College of
Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul
National University, Seoul, Korea; and Department of Pharmacology and
Institute of Biomedical Science (C.H.L.), College of Medicine, Hanyang
University, Seoul, Korea
Ceramide, formed by sphingomyelinase, is involved in the expression of
cyclooxygenase-2 (COX-2). This study examines the effect of C2-ceramide
(C2), a cell-permeable ceramide analog, on the lipopolysaccharide
(LPS)-inducible COX-2 expression and signaling pathways. C2 did not
induce COX-2 but potentiated LPS-inducible COX-2 expression in Raw264.7
cells, whereas dihydro-C2 was inactive. Treatment of cells with C2
notably increased LPS-inducible CCAAT/enhancer binding protein (C/EBP)
DNA binding. Antibody supershift experiments revealed that LPS-induced
C/EBP DNA binding activity depended on C/EBP
and C/EBP
but not
C/EBP
, C/EBP
or CBP/p300. C/EBP contributed to C2-enhanced DNA
binding activity.
4-(4-Fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl) 1H-imidazole
(SB203580), a p38 kinase inhibitor, completely inhibited LPS-inducible
and C2-potentiated LPS-inducible COX-2 expression. Enhancement of
LPS-inducible COX-2 expression and C/EBP DNA binding by C2 was
abrogated in dominant-negative mutant of JNK1 [JNK1(
)] cells.
2'-Amino-3'-methoxyflavone (PD98059) or stable transfection with
dominant-negative mutant of MKK1 decreased COX-2 induction by LPS but
failed to inhibit C2-enhanced LPS induction of COX-2. Transfection with
dominant-negative mutant of C/EBP inhibited the ability of C2 to
potentiate the induction of COX-2 by LPS. In LPS-treated cells, C2
enhanced both the nuclear translocation and the expression of
LPS-inducible C/EBP with an increase in AP-1 DNA binding activity.
These enhancements were abolished by JNK1() transfection. AP-1 decoy
oligonucleotide suppressed C2-potentiated C/EBP expression,
indicating that AP-1 was responsible for C2-mediated C/EBP
expression. These results demonstrate that C2 increases C/EBP-mediated COX-2 induction by LPS and that the pathway of JNK1
but not ERK1/2 is responsible for C/EBP activation involving activator protein-1-mediated enhanced C/EBP expression.
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