Parenchymal transforming growth factor beta-1: its type II receptor and Smad signaling pathway correlate with inflammation and fibrosis in chronic liver disease of viral etiology.
OBJECTIVE
Transforming growth factor-beta (TGF-beta) system is involved in the control of cell growth and extracellular matrix formation. Previous studies in patients with chronic liver disease have shown that increased TGF-beta expression significantly correlates with the degree of hepatic fibrosis. The aim of our study was to define TGF-beta system expression in hepatic parenchymal cells and its significance in patients with differing extents of chronic liver disease of viral etiology.


METHODS
Expression of TGF-beta 1, TGF-beta 1 type II receptor (TGF-beta RII) and the Smad signaling pathway was evaluated in consecutive liver sections of 77 patients with chronic liver disease (65 HCV positive and 12 HBV positive). Results were correlated with histological scores and apoptotic activity.


RESULTS
TGF-beta 1 was demonstrated in the liver of 30/56 (53.6%) patients with chronic hepatitis and 20/21 (95%) patients with cirrhosis, but in none of the 20 normal livers. Positive cytokine reaction was seen both in stromal cells and hepatocytes. Expression of TGF-beta RII and Smad proteins showed a distribution pattern similar to that of TGF-beta, with a direct correlation in terms of immunoreactivity extent. A significant correlation was found between parenchymal expression of TGF-beta system and inflammatory and fibrosis scores. No correlation was found with apoptotic index and other morphological, clinical or virological parameters.


CONCLUSIONS
The TGF-beta system is up-regulated at the ligand, receptor and signaling level in the liver of patients with more active disease. The strong expression of TGF-beta and the Smad pathway in parenchymal cells suggests that hepatocytes, in addition to mesenchymal cells, may play an important role in the progression of liver disease.
Calabrese
Fiorella
F
Department of Pathology, University of Padua, Italy. fiorella.calabrese@unipd.it
Valente
Marialuisa
M
Giacometti
Cinzia
C
Pettenazzo
Elena
E
Benvegnu
Luisa
L
Alberti
Alfredo
A
Gatta
Angelo
A
Pontisso
Patrizia
P
D000293:Adolescent; D000328:Adult; D017209:Apoptosis / Q000502:physiology; D016022:Case-Control Studies; D002908:Chronic Disease; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005260:Female; D006509:Hepatitis B / Q000378:metabolism*; D006526:Hepatitis C / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008103:Liver Cirrhosis / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D015398:Signal Transduction; D051785:Smad Proteins; D015534:Trans-Activators / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D053773:Transforming Growth Factor beta1; D015854:Up-Regulation
D004268:DNA-Binding Proteins; D018125:Receptors, Transforming Growth Factor beta; D051785:Smad Proteins; C508960:TGFB1 protein, human; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II