All-trans-retinoic acid ameliorates carbon tetrachloride-induced liver fibrosis in mice through modulating cytokine production.
OBJECTIVE
Liver fibrosis with any aetiology, induced by the transdifferentiation and proliferation of hepatic stellate cells (HSCs) to produce collagen, is characterized by progressive worsening in liver function, leading to a high incidence of death. We have recently reported that all-trans-retinoic acid (ATRA) suppresses the transdifferentiation and proliferation of lung fibroblasts and prevents radiation- or bleomycin-induced lung fibrosis.


METHODS
We examined the impact of ATRA on carbon tetrachloride (CCl(4))-induced liver fibrosis. We performed histological examinations and quantitative measurements of transforming growth factor (TGF)-beta1 and interleukin (IL)-6 in CCl(4)-treated mouse liver tissues with or without the administration of ATRA, and investigated the effect of ATRA on the production of the cytokines in quiescent and activated HSCs.


RESULTS
CCl(4)-induced liver fibrosis was attenuated in histology by intraperitoneal administration of ATRA, and the overall survival rate at 12 weeks was 26.5% without ATRA (n=25), whereas it was 75.0% (n=24) in the treatment group (P=0.0187). In vitro studies disclosed that the administration of ATRA reduced (i) the production of TGF-beta1, IL-6 and collagen from HSCs, (ii) TGF-beta-dependent transdifferentiation of the cells and IL-6-dependent cell proliferation and (iii) the activities of nuclear factor-kappaB p65 and p38mitogen-activated protein kinase, which stimulate the production of TGF-beta1 and IL-6, which could be the mechanism underlying the preventive effect of ATRA on liver fibrosis.


CONCLUSIONS
Our findings indicate that ATRA ameliorates liver fibrosis. As the oral administration of the drug results in good compliance, ATRA could be a novel approach in the treatment of liver fibrosis.
Hisamori
Shigeo
S
Department of Gastrointestinal Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan. kuboflt@kuhp.kyoto-u.ac.jp
Tabata
Chiharu
C
Kadokawa
Yoshio
Y
Okoshi
Kae
K
Tabata
Rie
R
Mori
Akira
A
Nagayama
Satoshi
S
Watanabe
Go
G
Kubo
Hajime
H
Sakai
Yoshiharu
Y
D000818:Animals; D002252:Carbon Tetrachloride Poisoning / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D054338:Cell Transdifferentiation / Q000187:drug effects; D003094:Collagen / Q000096:biosynthesis; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000378:metabolism; D007274:Injections, Intraperitoneal; D015850:Interleukin-6 / Q000378:metabolism*; D008099:Liver / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D014212:Tretinoin / Q000627:therapeutic use*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D015850:Interleukin-6; D016328:NF-kappa B; D012333:RNA, Messenger; D053773:Transforming Growth Factor beta1; D014212:Tretinoin; D003094:Collagen; D048051:p38 Mitogen-Activated Protein Kinases