Variable expression of cystatin C in cultured trans-differentiating rat hepatic stellate cells.
OBJECTIVE
To study the expression of cystatin C (CysC), its regulation by transforming growth factor-beta1 (TGF-beta1) and platelet-derived growth factor (PDGF) and the potential interference of CysC with TGF-beta1 signaling in this special cell type.


METHODS
We evaluated the CysC expression in cultured, profibrogenic hepatic stellate cells and trans-differentiated myofibroblasts by Northern and Western blotting and confocal laser scanning microscopy.


RESULTS
CysC was increased significantly in the course of trans-differentiation. Both TGF-beta1 and PDGF-BB suppressed CysC expression. Furthermore, CysC secretion was induced by the treatment with TGF-beta1. Although CysC induced an increased binding affinity of TGF-beta receptor type III (beta-glycan) as assessed by chemical cross-linking with [125I]-TGF-beta1, it did not modulate TGF-beta1 signal transduction as shown by evaluating the Smad2/3 phosphorylation status and [CAGA]-MLP-luciferase reporter gene assay. Interestingly, the shedding of type III TGF-beta receptor beta-glycan was reduced in CysC-treated cells. Our data indicated that CysC expression was upregulated during trans-differentiation.


CONCLUSIONS
Increased CysC levels in the serum of patients suffering from liver diseases are at least partially due to a higher expression in activated hepatic stellate cells. Furthermore, TGF-beta1 influences the secretion of CysC, highlighting a potentially important role of cysteine proteases in the progression of hepatic fibrogenesis.
Gressner
Axel M
AM
Institute of Clinical Chemistry and Pathobiochemistry, RWTH Aachen University, D-52074 Aachen, Germany. gressner@rwth-aachen.de
Lahme
Birgit
B
Meurer
Steffen K
SK
Gressner
Olav
O
Weiskirchen
Ralf
R
D000818:Animals; D001483:Base Sequence; D000077214:Becaplermin; D002454:Cell Differentiation; D002478:Cells, Cultured; D055316:Cystatin C; D015891:Cystatins / Q000235:genetics / Q000378:metabolism*; D018076:DNA, Complementary / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D011509:Proteoglycans / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis; D051381:Rats; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D053773:Transforming Growth Factor beta1
C525030:CST3 protein, human; C525032:Cst3 protein, rat; D055316:Cystatin C; D015891:Cystatins; D018076:DNA, Complementary; D010982:Platelet-Derived Growth Factor; D011509:Proteoglycans; D020574:Proto-Oncogene Proteins c-sis; D018125:Receptors, Transforming Growth Factor beta; C508960:TGFB1 protein, human; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; C071736:betaglycan; D000077214:Becaplermin