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1 Histology, Microbiology and Medical Biotechnologies, University of Padua, Padua, Italy; Gastroenterological Sciences, University of Padua, Padua, Italy
2 Histology, Microbiology and Medical Biotechnologies, University of Padua, Padua, Italy
3 Institute of Internal Medicine, University of Florence, Florence, Italy
4 Gastroenterological Sciences, University of Padua, Padua, Italy
* To whom correspondence should be addressed. E-mail: ignazio.castagliuolo{at}unipd.it.
Activated hepatic stellate cells (HSCs) secrete extracellular matrix components during hepatic
fibrosis, but recent studies have shown that HSCs can also release a variety of pro-inflammatory
cytokines. Moreover, bacterial endotoxemia is not only associated with systemic complications in the
late stages of liver failure, it is also a direct cause of liver damage, activating resident inflammatory
cells. In this paper, we investigated whether HSCs can respond directly to bacterial cell wall products
acquiring a new phenotype.
RT-PCR and immunocytochemistry assays were used to show that murine HSCs expressed
specific mRNA transcripts and proteins for lipopolysaccharide (LPS) and lipoteichoic acid (LTA)
receptor systems, and peptidoglycan recognition proteins (PGRPs). Exposing HSCs to bacterial
endotoxins led to phosphorylation of mitogen-activated protein kinase ERK1 and the development of a
pro-inflammatory phenotype. After exposure to LPS, LTA or N-acetyl muramyl peptide (NAM), TGF-
1, IL-6 and MCP-1 mRNA specific transcripts and proteins increased significantly in HSCs, as
assayed by quantitative real-time RT-PCR and ELISA. These LPS-mediated effects in HSCs were
receptor dependent, since LPS-induced ERK1 phosphorylation, IL-6 and MCP-1 mRNA and protein
levels up-regulation were significantly less pronounced in HSCs isolated from C3H/HeJ mice lacking
TLR4.
In conclusion, our results show that murine HSCs express functional receptors for bacterial
endotoxins and HSCs exposed to bacterial products develop a strong pro-inflammatory phenotype. We
speculate that high levels of bacterial endotoxins in the portal vein may directly induce a proinflammatory
phenotype in HSCs that contributes to liver damage.
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