Exposure to bacterial cell wall products triggers an inflammatory phenotype in hepatic stellate cells.
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 proinflammatory cytokines. Moreover, bacterial endotoxemia is not only associated with systemic complications in the late stages of liver failure but is also a direct cause of liver damage, activating resident inflammatory cells. In this study, 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 LPS and lipoteichoic acid (LTA) receptor systems and peptidoglycan recognition proteins. Exposing HSCs to bacterial endotoxins led to phosphorylation of mitogen-activated protein kinase ERK1 and the development of a proinflammatory phenotype. After exposure to LPS, LTA, or N-acetyl muramyl peptide, transforming growth factor-beta1, IL-6, and monocyte chemoattractant protein-1 (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, because LPS-induced ERK1 phosphorylation, IL-6, and MCP-1 mRNA and protein level upregulation were significantly less pronounced in HSCs isolated from C3H/HeJ mice lacking Toll-like receptor 4. In conclusion, our results show that murine HSCs express functional receptors for bacterial endotoxins, and HSCs exposed to bacterial products develop a strong proinflammatory 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.
Brun
Paola
P
Department of Histology, University of Padua, Padua, Italy.
Castagliuolo
Ignazio
I
Pinzani
Massimo
M
Palù
Giorgio
G
Martines
Diego
D
D000818:Animals; D001427:Bacterial Toxins / Q000378:metabolism* / Q000633:toxicity*; D002473:Cell Wall; D016207:Cytokines / Q000096:biosynthesis; D004797:Enzyme-Linked Immunosorbent Assay; D020869:Gene Expression Profiling; D007150:Immunohistochemistry; D007249:Inflammation; D008070:Lipopolysaccharides / Q000633:toxicity; D008099:Liver / Q000166:cytology* / Q000276:immunology / Q000473:pathology*; D008103:Liver Cirrhosis / Q000503:physiopathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D010641:Phenotype; D011169:Portal Vein; D012333:RNA, Messenger / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013682:Teichoic Acids / Q000633:toxicity; D015854:Up-Regulation
D001427:Bacterial Toxins; D016207:Cytokines; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D013682:Teichoic Acids; C009900:lipoteichoic acid