Fibrillin-1 expression in normal and fibrotic rat liver and in cultured hepatic fibroblastic cells: modulation by mechanical stress and role in cell adhesion.
Fibrillin-1, together with elastin, is the main component of elastic fibers found throughout the extracellular space and responsible for the biomechanical properties of most tissues and organs. In this work, fibrillin-1 expression and modulation were explored in experimental rat liver fibrosis and in vitro; furthermore, the role of fibrillin-1 fragments on cell adhesion was analyzed. Fibrosis was induced by subjecting rats to common bile duct ligation for 72 h and 7 days or carbon tetrachloride (CCl(4)) treatment for 2 and 6 weeks. Immunohistochemistry showed that, after bile duct ligation, fibrillin-1, elastin, and alpha-smooth muscle actin colocalized in the developing portal connective tissue. In CCl(4)-treated animals, a similar colocalization was observed in septa; however, elastin deposition was not observed around activated alpha-smooth muscle actin-positive stellate cells of the parenchyma. Treatment with the profibrogenic mediator transforming growth factor-beta1 (TGF-beta1) greatly increased the fibrillin-1 expression of cultured liver fibroblasts. The level of fibrillin-1 expression was significantly higher in cells grown in restrained (stressed) collagen lattices compared with those grown in unrestrained collagen lattices. Cell adhesion on the C-terminal fragment of fibrillin-1 containing the RGD sequence (rF6H) slightly increased (between 0.3 and 2.5 microg/ml) and decreased at higher concentrations, while adhesion on the N-terminal fragment of fibrillin-1 (rF16) was dose-dependently decreased. In addition, the rF16 fragment decreased cell adhesion to fibronectin. In conclusion, our study illustrates the important deposition of fibrillin-1 that occurs in two mechanistically distinct settings of liver fibrogenesis. Furthermore, the induction of fibrillin-1 expression by TGF-beta1 and mechanical stress, and the antiadhesive properties of fibrillin-1 fragments suggest important implications for physiological and pathological fibrillin-1 catabolism during tissue remodeling.
Lorena
Dionne
D
Groupe de Recherches pour l'Etude du Foie, INSERM E0362, and Institut Fédératif de Recherche 66, Pathologies Infectieuses et Cancers, Université Victor Segalen Bordeaux 2, Bordeaux, France.
Darby
Ian A
IA
Reinhardt
Dieter P
DP
Sapin
Vincent
V
Rosenbaum
Jean
J
Desmoulière
Alexis
A
D000199:Actins / Q000378:metabolism; D000818:Animals; D002448:Cell Adhesion / Q000502:physiology; D002461:Cell Line, Transformed; D003094:Collagen; D004547:Elastic Tissue; D004549:Elastin / Q000378:metabolism; D000071838:Fibrillin-1; D000071837:Fibrillins; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007124:Immunoenzyme Techniques; D007537:Isometric Contraction; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008103:Liver Cirrhosis / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D020894:Microfibrils / Q000502:physiology; D008840:Microfilament Proteins / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013314:Stress, Mechanical; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D053773:Transforming Growth Factor beta1; D054392:Adipokines
D000199:Actins; D003094:Collagen; D004549:Elastin; D000071838:Fibrillin-1; D000071837:Fibrillins; D008840:Microfilament Proteins; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; C000605722:FBN1 protein, human; D054392:Adipokines; C000605725:Fbn1 protein, rat; C508960:TGFB1 protein, human; C508962:Tgfb1 protein, rat