Involvement of integrin-linked kinase in carbon tetrachloride–induced hepatic fibrosis in rats

Abstract

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 CCl 4 -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. (HEPATOLOGY 2006;44:612-622.)

Hepatic stellate cells require a stiff environment for myofibroblastic differentiation

“…The mechanism for sensing and transmitting mechanical signals has not been identified in HSC, but, based on data in the literature from other systems, almost certainly involves integrins, their interactions with the cytoskeleton, and downstream signaling networks (3,32). Investigators studying HSC have demonstrated that RGD sequence-mediated interactions, as well as integrin-linked kinase and possibly focal adhesion kinase, are required for HSC differentiation, consistent with the stiffness and matrix dependence we describe (20,34,35,44). Further investigation will be required to determine the role of integrins in HSC mechanotransduction.…”

JNK1 determines the oncogenic or tumor-suppressive activity of the integrin-linked kinase in human rhabdomyosarcoma

“…Analysis of canonical ILK-regulated phosphorylation sites, such as Ser473-Akt and Ser9-GSK3β (32,33), demonstrated similar reductions in both ARMS and ERMS cells in response to ILK siRNA (data not shown), which suggests that alternative pathways were involved in the disparate growth effects in ERMS versus ARMS. ILK has previously been demonstrated to indirectly regulate the phosphorylation of members of the MAPK signaling family (14,34,35). Analysis of the phosphorylated MAPKs ERK1 and ERK2 demonstrated similar results to Akt and GSK3β (data not shown).…”

Transforming growth factor-β and substrate stiffness regulate portal fibroblast activation in culture

“…Potential mechanosensors such as integrins along with their downstream signaling pathways might be attractive therapeutic targets. 48,49 In summary, we have characterized portal fibroblast activation in vitro and have demonstrated that both TGF-␤ and matrix stiffness are critical for activation to occur. The demonstration that PFs and HSCs are morphologically, geographically, and functionally distinct may have important implications for both the study and treatment of fibrosis.…”