Transforming growth factor betas and their receptors in human liver cirrhosis

Background Transforming growth factor betas (TGF-beta s) are a group of hom ologous polypeptides that exert pleiotropic effects on various cell types a nd stimulate the formation of extracellular matrix and fibrosis. To evaluat e whether TGF-beta isoforms (TGF-beta 1, TGF-beta 2 and TGF-beta 3) and the ir receptors (types I-III) are also of importance in the pathophysiology of liver cirrhosis, we analysed their concomitant expression and localization in human liver cirrhosis. Patients Cirrhotic liver tissue samples were obtained from 17 patients (fou r 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. Methods The tissues were fixed in Bouin's solution and paraffin-embedded fo r histological analysis. For RNA analysis, freshly obtained tissue samples were snap-frozen in liquid nitrogen and stored at -80 degrees C until analy sed. Northern blot analysis was used to examine the expression of TGF-beta 1, beta 2 and beta 3 and their receptors, type I (TPR-I), type II (TPR-II) and type III (TPR-III), Immunohistochemistry was performed to determine the localization of the corresponding proteins in the normal and the cirrhotic liver. Results Northern blot analysis revealed enhanced expression (P < 0.05) of T GF-beta 1 (twofold increase), TGF-beta 2 (threefold increase) and TGF-beta 3 (8.5-fold increase) and of TPR-II (threefold increase) mRNA in liver cirr hosis in comparison with normal controls. In contrast, T beta R-I (ALK-5) a nd T beta R-III mRNA expression showed no significant changes, No TGF-beta isoform immunoreactivity was present in hepatocytes in either normal livers or in liver cirrhosis. However, in liver cirrhosis, intense TGF-beta 1 imm unoreactivity was present in bile duct and ductular epithelial cells (inclu ding ductular proliferations) and in inflammatory cells, In a few sinusoida l lining cells, faint TGF-beta 1 and moderate TGF-beta 2 immunoreactivity w as present. TGF-beta 3 immunostaining was present in bile duct and ductular epithelial cells, in inflammatory cells and in fibroblast-like spindle cel ls in liver cirrhosis, For T beta R-I and T beta R-II, the immunoreactivity was localized in hepatocytes and biliary cells in normal and cirrhotic liv er tissues, with higher intensity for T beta R-II in the cirrhotic liver. Conclusion Enhanced expression of all three TGF-beta isoforms and of T beta R-II in liver cirrhosis suggests their involvement in this fibrotic disord er. The higher immunoreactivity of the three TGF-beta isoforms in the bile duct epithelial cells in cirrhotic tissues suggests a possible role of thes e cells in the pathogenesis of liver cirrhosis, Eur J Gastroenterol Hepatol 10:1031-1039 (C) 1998 Lippincott Williams & Wilkins.