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J. Biol. Chem., Vol. 281, Issue 34, 24863-24872, August 25, 2006

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The Role of Integrin-linked Kinase in Liver Wound Healing^*

From the Division of Digestive and Liver Diseases, Department of Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390-8887

Liver wound healing is an integrated process in which hepatic stellate cells play a major role. We hypothesized that the cellextracellular signaling protein integrin-linked kinase (ILK) is important in transducing signals from the extracellular matrix to stellate cells and thus plays a critical role in stellate cell activation and fibrogenesis during liver injury. Liver injury and subsequent stellate cell activation led to a 3-fold increase in ILK expression and increased kinase activity. Overexpression of ILK in isolated stellate cells led to enhanced motility and adhesion as well as increases in smooth muscle -actin and type I collagen mRNA expression. The effects of ILK on stellate cell phenotypes were phosphatidylinositol 3-kinase-dependent. Forced expression of ILK in vivo led to increases in type I collagen, smooth muscle -actin, transforming growth factor-, and extra domain A (EDA) fibronectin mRNAs (by 3.2-, 3.5-, 2.5-, and 2.2-fold, respectively; n = 8, p < 0.05 for each versus the control), whereas inhibition of ILK in vivo led to significant reductions in these mRNAs. Morphometric analysis revealed that ILK overexpression led to a 31.4% increase in liver collagen content (n = 8, p < 0.05 versus the control); in contrast ILK knockdown in vivo led to a significant reduction in fibrogenesis. We conclude that ILK plays an important pathophysiological role in vivo in liver wound healing.

Received for publication, December 21, 2005 , and in revised form, April 26, 2006.

^* This work was supported by National Institutes of Health Grants R01 DK 50574 and R01 DK 60338 (to D. C. R.) and the Burroughs Wellcome Fund. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Recipient of a Burroughs Wellcome Fund Translational Scientist Award. To whom correspondence should be addressed: Div. of Digestive and Liver Diseases, University of Texas Southwestern Medical Ctr., 5323 Harry Hines Blvd., Dallas, TX 75390-8887. Tel.: 214-648-3444; Fax: 214-648-0274; E-mail: don.rockey{at}utsouthwestern.edu.

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