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World J Gastroenterol. 2010 Jan 14;16(2):210-6.

Liver myofibroblasts activate protein C and respond to activated protein C.

Author information

  • 1INSERM U889, Victor Segalen Bordeaux 2 University, F-33076 Bordeaux, France.

Abstract

AIM:

To study the protein C activation system in human liver myofibroblasts, and the effects of activated protein C (APC) on these cells.

METHODS:

Human liver myofibroblasts were obtained by outgrowth. Expression of protease activated receptor 1 (PAR-1), endothelial protein C receptor (EPCR) and thrombomodulin (TM) was analyzed by flow cytometry. Extracellular signal-regulated kinase (ERK)1/2 activation was assessed by Western blotting using anti-phospho-ERK antibodies. Collagen synthesis was studied with real-time reverse transcription-polymerase chain reaction (RT-PCR). Activation of protein C was studied by incubating liver myofibroblasts with zymogen protein C in the presence of thrombin and detecting the generation of APC with a colorimetric assay using a peptide substrate.

RESULTS:

Primary cultures of human liver myofibroblasts expressed EPCR on their surface, together with PAR-1 and TM. This receptor system was functional since exposure of myofibroblasts to APC induced ERK1/2 phosphorylation in a dose- and time-dependent manner. Furthermore, APC significantly upregulated the expression of collagen mRNA, as shown by real-time RT-PCR. Collagen upregulation was controlled through the ERK pathway as it was inhibited when using the mitogen-activated protein/extracellular signal-regulated kinase kinase inhibitor PD98059. Finally, using a cell-based colorimetric assay, we showed that intact myofibroblasts converted protein C into APC in the presence of thrombin.

CONCLUSION:

These data suggest that APC is a new modulator of liver myofibroblast activity and contributes to the pathophysiology of chronic liver diseases.

PMID:
20066740
[PubMed - indexed for MEDLINE]
PMCID:
PMC2806559
Free PMC Article

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