Regulation of cyclooxygenase 2 expression in hepatocytes by CCAAT/enhancer-binding proteins.
OBJECTIVE
Expression of cyclooxygenase (COX)-2 in response to lipopolysaccharide (LPS) challenge has been analyzed in cultured fetal, neonatal, and adult hepatocytes and in hepatoma cell lines.


METHODS
To study the mechanisms of LPS-dependent expression of COX-2 in these cells, the activity of the COX-2 promoter and the levels of CCAAT/enhancer-binding proteins (C/EBPs) were determined.


RESULTS
COX-2 was induced in fetal hepatocytes, but this response declined rapidly after birth. This loss of inducibility of COX-2 paralleled the expression of C/EBP-alpha in neonatal hepatocytes. Transfection of fetal and adult hepatocytes with sequences corresponding to the 5'-flanking region of the rat COX-2 gene confirmed the absence of promoter activity in adult hepatocytes. Moreover, transient expression of C/EBP-alpha, but not C/EBP-delta, in the hepatoma cell line AT3F cells abolished the COX-2 promoter activity. Prolonged culture of adult hepatocytes restored the induction of COX-2 after complete disappearance of C/EBP-alpha.


CONCLUSIONS
These results suggest that the presence of high levels of C/EBP-alpha is involved in the impairment of COX-2 expression in adult hepatocytes challenged with proinflammatory stimuli.
Instituto de Bioquímica, Centro Mixto Consejo Superior de Investigaciones Cientificas-Universidad Complutense, Facultad de Farmacia, Universidad Complutense, Madrid, Spain.
N A
NA
Callejas
L
L
Boscá
C S
CS
Williams
R N
RN
DuBOIS
P
P
Martín-Sanz
D000367:Age Factors; D000818:Animals; D015153:Blotting, Western; D022762:CCAAT-Enhancer-Binding Proteins; D006528:Carcinoma, Hepatocellular; D051546:Cyclooxygenase 2; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D005333:Fetus / Q000166:cytology / Q000201:enzymology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology; D007527:Isoenzymes / Q000032:analysis / Q000235:genetics*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000166:cytology / Q000201:enzymology*; D008861:Microsomes / Q000201:enzymology; D009687:Nuclear Proteins / Q000235:genetics*; D011247:Pregnancy; D011451:Prostaglandin-Endoperoxide Synthases / Q000032:analysis / Q000235:genetics*; D051381:Rats; D017208:Rats, Wistar; D015533:Transcriptional Activation / Q000187:drug effects / Q000502:physiology; D014162:Transfection; D014407:Tumor Cells, Cultured
D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D007527:Isoenzymes; D008070:Lipopolysaccharides; D009687:Nuclear Proteins; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases