Regulation of cyclooxygenase 2 expression in hepatocytes by CCAAT/enhancer-binding proteins

Gastroenterology. 2000 Aug;119(2):493-501. doi: 10.1053/gast.2000.9374.


Background & aims: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • Animals
  • Blotting, Western
  • CCAAT-Enhancer-Binding Proteins
  • Carcinoma, Hepatocellular
  • Cyclooxygenase 2
  • DNA-Binding Proteins / genetics*
  • Female
  • Fetus / cytology
  • Fetus / enzymology
  • Gene Expression Regulation, Enzymologic / drug effects
  • Gene Expression Regulation, Enzymologic / physiology
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Expression Regulation, Neoplastic / physiology
  • Isoenzymes / analysis
  • Isoenzymes / genetics*
  • Lipopolysaccharides / pharmacology
  • Liver / cytology
  • Liver / enzymology*
  • Microsomes / enzymology
  • Nuclear Proteins / genetics*
  • Pregnancy
  • Prostaglandin-Endoperoxide Synthases / analysis
  • Prostaglandin-Endoperoxide Synthases / genetics*
  • Rats
  • Rats, Wistar
  • Transcriptional Activation / drug effects
  • Transcriptional Activation / physiology
  • Transfection
  • Tumor Cells, Cultured


  • CCAAT-Enhancer-Binding Proteins
  • DNA-Binding Proteins
  • Isoenzymes
  • Lipopolysaccharides
  • Nuclear Proteins
  • Cyclooxygenase 2
  • Prostaglandin-Endoperoxide Synthases