Remote delivery and expression of soluble type II TGF-beta receptor in muscle prevents hepatic fibrosis in rats.

Abstract

Transforming growth factor-beta (TGF-beta) has been implicated in the process of hepatic fibrosis, and stimulates production of extracellular matrix in hepatic stellate cells, which play a major role in the process. It has been recently reported that blockage of TGF-beta signaling prevents hepatic fibrosis. We evaluated a strategy for anti-TGF-beta gene therapy for hepatic fibrosis by transfecting plasmids expressing an entire extracellular domain of human TGF-beta type II [soluble type II TGF-beta receptor (sTGF-betaIIR)] into skeletal muscle in a rat experimental model of dimethylnitrosamine- (DMN-) induced fibrosis. sTGF-betaIIR treatment decreased significantly the occurrence of DMN-induced hepatic fibrosis, evaluated by computed image analysis and by measurement of hydroxyproline content of the liver, and reduced the expression of collagen and alpha-smooth muscle actin. The treatment also caused a significant decrease in hepatic levels of interleukin- (IL-) 12 (Th1 cytokine) and an increase in those of IL-10 (Th2 cytokine), indicating a change in the Th1/Th2 cytokine balance in the liver. In conclusion, blockade of TGF-beta after intramuscular transfer of the soluble type II TGF-beta receptor gene suppressed hepatic fibrosis, suggesting that this strategy may be useful for gene therapy of hepatic fibrosis.

• Authors: Makoto Nakamuta, Shusuke Morizono, Satoru Tsuruta, Motoyuki Kohjima, Kazuhiro Kotoh, Munechika Enjoji
• Journal: International journal of molecular medicine (Int J Mol Med) Vol. 16 Issue 1 Pg. 59-64 (Jul 2005) ISSN: 1107-3756 [Print] Greece
• PMID: 15942678 (Publication Type: Journal Article)

Chemical References

• Actins
• Collagen Type I
• RNA, Messenger
• Receptors, Transforming Growth Factor beta
• smooth muscle actin, rat
• Interleukin-10
• Interleukin-12
• Protein Serine-Threonine Kinases
• Receptor, Transforming Growth Factor-beta Type II
• Dimethylnitrosamine

Topics

• Actins (genetics)
• Animals
• Body Weight (drug effects)
• Collagen Type I (genetics)
• Dimethylnitrosamine (pharmacology)
• Gene Expression Regulation
• Humans
• Interleukin-10 (metabolism)
• Interleukin-12 (metabolism)
• Liver Cirrhosis (chemically induced, metabolism, pathology, prevention & control)
• Male
• Muscles (metabolism)
• Organ Size (drug effects)
• Protein Serine-Threonine Kinases
• RNA, Messenger (genetics)
• Rats
• Rats, Wistar
• Receptor, Transforming Growth Factor-beta Type II
• Receptors, Transforming Growth Factor beta (genetics, metabolism)
• Solubility