SERPINB3 modulates TGF-beta expression in chronic liver disease.
Transforming growth factor-beta1 (TGF-beta1) is the master cytokine in the pathogenesis of liver fibrosis. TGF-beta1 and extent of fibrosis were correlated recently to the serpin SERPINB3 in idiopathic pulmonary fibrosis, a chronic disease recalling liver cirrhosis. The aim of this study was to assess the relation between SERPINB3, TGF-beta1 and fibrosis in chronic liver diseases and to determine the effect of this serpin on TGF-beta1 expression using in vitro models. SERPINB3 and TGF-beta1 were evaluated in liver biopsies of 94 patients with chronic liver disease. The effect of SERPINB3 on TGF-beta1 expression was determined in primary human hepatocytes, HepG2 and Huh7 cells transfected with intact SERPINB3 human gene or with reactive site loop deleted mutants. A significant correlation between TGF-beta1 and SERPINB3 at the protein level was observed in liver biopsies, confirmed by a positive correlation at mRNA level. Both proteins were correlated to the extent of liver fibrosis. All transfected cells showed increased TGF-beta1 mRNA and protein production and the integrity of the reactive site loop of the serpin was crucial to achieve this effect. In conclusion, chronically damaged hepatocytes produce SERPINB3 and TGF-beta, and the anti-protease activity of this serpin might be implicated in TGF-beta1 induction.
Turato
Cristian
C
I.O.V. (IRCCS), Padua, Italy.
Calabrese
Fiorella
F
Biasiolo
Alessandra
A
Quarta
Santina
S
Ruvoletto
Mariagrazia
M
Tono
Natascia
N
Paccagnella
Daniela
D
Fassina
Giorgio
G
Merkel
Carlo
C
Harrison
Tim J
TJ
Gatta
Angelo
A
Pontisso
Patrizia
P
D000328:Adult; D000368:Aged; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism*; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D005260:Female; D005455:Fluorescent Antibody Technique; D015870:Gene Expression; D006801:Humans; D008099:Liver / Q000473:pathology; D008103:Liver Cirrhosis / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D015843:Serpins / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*
D000951:Antigens, Neoplasm; D015843:Serpins; D053773:Transforming Growth Factor beta1; C051072:squamous cell carcinoma-related antigen