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

Abstract

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. 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. 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. 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.