Involvement of integrin-linked kinase in carbon tetrachloride-induced hepatic fibrosis in rats.
Integrin-linked kinase (ILK) is a multidomain focal adhesion protein implicated in signal transduction between integrins and growth factor receptors. Although its expression is upregulated in pulmonary and renal fibrosis, its role in the development of hepatic fibrosis remains to be determined. Therefore, we considered it important to investigate whether ILK is involved in activation of hepatic stellate cells and thus plays a role in the development of hepatic fibrosis. Immunohistochemical analysis of liver sections obtained from rats with CCl4-induced cirrhosis revealed increased expression and colocalization of ILK and alpha-smooth muscle actin in hepatic stellate cells in perisinusoidal areas. In addition, hepatic stellate cells isolated from fibrotic livers expressed high levels of ILK and alpha-smooth muscle actin, and their expression was sustained in culture. In contrast, hepatic stellate cells (HSCs) isolated from normal rat liver did not express ILK, but its expression was increased when the cells were activated in culture. Our studies also showed that ILK is involved in the phosphorylation of ERK 1/2, p38 MAPK, JNK, and PKB and that selective inhibition of ILK expression by siRNA results in a significant decrease in their phosphorylation. These changes were accompanied by significant inhibition of cell spreading and migration without affecting cell proliferation. In conclusion, ILK plays a key role in HSC activation and could be a possible target for antifibrogenic therapy.
Zhang
Yining
Y
Graduate School of Comprehensive Human Science, University of Tsukuba, Tsukaba City, and Division of Gastroenterology and Hepatology, Tokyo Medical University Kasumigaura Hospital, Japan.
Ikegami
Tadashi
T
Honda
Akira
A
Miyazaki
Teruo
T
Bouscarel
Bernard
B
Rojkind
Marcos
M
Hyodo
Ichinosuke
I
Matsuzaki
Yasushi
Y
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002251:Carbon Tetrachloride / Q000633:toxicity; D049109:Cell Proliferation; D002478:Cells, Cultured; D018450:Disease Progression; D015870:Gene Expression; D007150:Immunohistochemistry; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology; D008297:Male; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D000099200:Scaffold Protein ILK
D002251:Carbon Tetrachloride; D017346:Protein Serine-Threonine Kinases; D034741:RNA, Small Interfering; D000099200:Scaffold Protein ILK