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.
Park
Ji-Hyun
JH
Department of Pathology, Catholic University of Daegu, College of Medicine, Nam-gu, Daegu, Republic of Korea.
Jo
Ji-Ho
JH
Kim
Kyung-Hyun
KH
Kim
Soo-Jung
SJ
Lee
Woo-Ram
WR
Park
Kwan-Kyu
KK
Park
Jae-Bok
JB
D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D002251:Carbon Tetrachloride / Q000633:toxicity*; D016207:Cytokines / Q000097:blood; D024202:Electrophoretic Mobility Shift Assay; D004797:Enzyme-Linked Immunosorbent Assay; D007150:Immunohistochemistry; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy*; D008111:Liver Function Tests; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009838:Oligodeoxyribonucleotides / Q000235:genetics / Q000627:therapeutic use*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016329:Sp1 Transcription Factor / Q000235:genetics*
D016207:Cytokines; D009838:Oligodeoxyribonucleotides; D016329:Sp1 Transcription Factor; D002251:Carbon Tetrachloride