The role of integrin-linked kinase in liver wound healing.
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 alpha-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 alpha-actin, transforming growth factor-beta, 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.
Shafiei
Mahnoush S
MS
Division of Digestive and Liver Diseases, Department of Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390-8887, USA.
Rockey
Don C
DC
D000818:Animals; D002478:Cells, Cultured; D003239:Connective Tissue Cells / Q000473:pathology / Q000502:physiology; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis; D008099:Liver / Q000201:enzymology* / Q000293:injuries / Q000473:pathology; D008115:Liver Regeneration / Q000502:physiology; D008297:Male; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D014945:Wound Healing / Q000502:physiology; D000099200:Scaffold Protein ILK
D016326:Extracellular Matrix Proteins; D017346:Protein Serine-Threonine Kinases; D000099200:Scaffold Protein ILK