Remote delivery and expression of soluble type II TGF-beta receptor in muscle prevents hepatic fibrosis in rats.
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.
Nakamuta
Makoto
M
Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan. nakamuta@intmed3.med.kyushu-u.ac.jp
Morizono
Shusuke
S
Tsuruta
Satoru
S
Kohjima
Motoyuki
M
Kotoh
Kazuhiro
K
Enjoji
Munechika
M
D000199:Actins / Q000235:genetics; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D024042:Collagen Type I / Q000235:genetics; D004128:Dimethylnitrosamine / Q000494:pharmacology; D005786:Gene Expression Regulation; D006801:Humans; D016753:Interleukin-10 / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D009132:Muscles / Q000378:metabolism*; D009929:Organ Size / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D012995:Solubility
D000199:Actins; D024042:Collagen Type I; D004128:Dimethylnitrosamine; D016753:Interleukin-10; D018664:Interleukin-12; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta; C498862:Acta2 protein, rat