Antifibrotic effect through the regulation of transcription factor using ring type-Sp1 decoy oligodeoxynucleotide in carbon tetrachloride-induced liver fibrosis.

BACKGROUND

Liver fibrosis is characterized by the excessive accumulation of extracellular matrix (ECM). Recent advances in the knowledge about the cellular, molecular and genetic aspects of fibrosis have opened a new era of research on liver cirrhosis. A transcription factor, Sp1, originally described as a ubiquitous transcription factor, is involved in the basal expression of ECM genes and may be important in the fibrotic processes.

METHODS

The chronic hepatic damage received intraperitoneal injection of carbon tetrachloride (2 mg/kg) dissolved in corn oil (1 : 3 ratio) three times a weekly for 8 weeks. The delivery of decoy oligodeoxynucleotide (ODN) was performed by injection of 10 microg of scrambled decoy ODN or 10 microg of ring type (R)-Sp1 decoy ODN through the mouse tail vein. All animals of each group were sacrificed, DNA binding activity, expression of cytokines and histological analysis were measured.

RESULTS

We have generated a R-Sp1 decoy ODN that effectively blocks Sp1 binding to the promoter region for transcription regulation of transforming growth factor (TGF)-beta1. The expression of fibrotic cytokines and inflammatory cytokines was decreased by using the R-Sp1 decoy ODN in liver cirrhosis.

CONCLUSIONS

The present study demonstrates that the R-Sp1 decoy ODN inhibits TGF-beta1 expression in liver cirrhosis. These results indicate that targeting Sp1 can efficiently block ECM expression, and suggest that such an approach may represent an interesting therapeutic alternative towards the treatment of cirrhosis.