Transforming growth factor betas and their receptors in human liver cirrhosis

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BackgroundTransforming growth factor betas (TGF-βs) are a group of homologous polypeptides that exert pleiotropic effects on various cell types and stimulate the formation of extracellular matrix and fibrosis. To evaluate whether TGF-β isoforms (TGF-β1, TGF-β2 and TGF-β3) and their receptors (types l-lll) are also of importance in the pathophysiology of liver cirrhosis, we analysed their concomitant expression and localization in human liver cirrhosis.PatientsCirrhotic liver tissue samples were obtained from 17 patients (four women, 13 men) with a median age of 41 years (range 22–67). Normal liver tissues from ten patients (seven women, three men) with a median age of 55 years (range 45–75) served as controls.MethodsThe tissues were fixed in Bouin's solution and paraffin-embedded for histological analysis. For RNA analysis, freshly obtained tissue samples were snapfrozen in liquid nitrogen and stored at −80°C until analysed. Northern blot analysis was used to examine the expression of TGF-β1, β2 and β3 and their receptors, type I (TβR-I), type II (TβR-ll) and type III (TβR-lll). Immunohistochemistry was performed to determine the localization of the corresponding proteins in the normal and the cirrhotic liver.ResultsNorthern blot analysis revealed enhanced expression (P<0.05) of TGF-β1 (twofold increase), TGF-β2 (threefold increase) and TGF-β3 (8.5-fold increase) and of TβR-ll (threefold increase) mRNA in liver cirrhosis in comparison with normal controls. In contrast, TβR-l (ALK-5) and TβR-lll mRNA expression showed no significant changes. No TGF-β isoform immunoreactivity was present in hepatocytes in either normal livers or in liver cirrhosis. However, in liver cirrhosis, intense TGF-β1 immunoreactivity was present in bile duct and ductular epithelial cells (including ductular proliferations) and In inflammatory cells. In a few sinusoidal lining cells, faint TGF-β1 and moderate TGF-β2 immunoreactivity was present TGF-β3 immunostaining was present in bile duet and ductular epithelial cells, in inflammatory cells and in fibroblast-like spindle cells in liver cirrhosis. For TβR-l and TβR-ll, the immunoreactivity was localized in hepatocytes and biliary cells in normal and cirrhotic liver tissues, with higher intensity for TβR-ll in the cirrhotic liver.ConclusionEnhanced expression of all three TGF-β isoforms and of TβR-ll in liver cirrhosis suggests, their involvement in this fibrotic disorder. The higher immunoreactivity of the three TGF-β isoforms in the bile duct epithelial cells in cirrhotic tissues suggests a possible role of these cells in the pathogenesis of liver cirrhosis.

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