Human paraoxonase-1 gene expression by HepG2 cells is downregulated by interleukin-10 and tumor necrosis factor-α, but is upregulated by interleukin-6

Recent studies have demonstrated that human paraoxonase-1 (PON1) associated with HDL, plays a role for anti-atherosclerotic effects of HDL, however, the relationships between PON1 and inflammatory cytokines remain unclear. To clarify this point, we evaluated the transcriptional regulation of PON1 gene by IL-1beta, IL-6 and TNF-alpha in HepG2 cells using luciferase reporter gene assay. We determined the nucleotide sequence of upstream of PON1 gene, and constructed plasmids containing various lengths of upstream region. In the plasmid constructs of U39 (PON1 upstream -1232/-6), U682 (-589/-6), U797 (-472/-6) and U953 (-318/-6), U953 showed a stepwise upregulation in basal promoter activity. The relative promoter activities using U682 plasmid were generally downregulated by IL-1beta and TNF-alpha,, but were upregulated by IL-6. By the combination of IL-1beta, IL-6 and/or TNF-alpha, the promoter activities were proportionally regulated. The result of PON1 transcriptional regulation by cytokines in HepG2 cells was confirmed to be concordant with that of regulation of PON1 mRNA expression by cytokines. These results suggest that PON1 mRNA expression by hepatocytes is regulated by proinflammatory cytokines and that proinflammatory cytokines secreted in a disease state, may play a role in the development of atherosclerotic lesion via modification of PON1 mRNA expression affecting on the anti-oxidative property of HDL. (C) 2003 Elsevier Inc. All rights reserved.