title: The transcriptomic response of rat hepatic stellate cells to endotoxin: implications for hepatic inflammation and immune regulation.
abstract: With their location in the perisinusoidal space of Disse, hepatic stellate cells (HSCs) communicate with all of the liver cell types both by physical association (cell body as well as cytosolic processes penetrating into sinusoids through the endothelial fenestrations) and by producing several cytokines and chemokines. Bacterial lipopolysaccharide (LPS), circulating levels of which are elevated in liver diseases and transplantation, stimulates HSCs to produce increased amounts of cytokines and chemokines. Although recent research provides strong evidence for the role of HSCs in hepatic inflammation and immune regulation, the number of HSC-elaborated inflammatory and immune regulatory molecules may be much greater then known at the present time. Here we report time-dependent changes in the gene expression profile of inflammatory and immune-regulatory molecules in LPS-stimulated rat HSCs, and their validation by biochemical analyses. LPS strongly up-regulated LPS-response elements (TLR2 and TLR7) but did not affect TLR4 and down-regulated TLR9. LPS also up-regulated genes in the MAPK, NFκB, STAT, SOCS, IRAK and interferon signaling pathways, numerous CC and CXC chemokines and IL17F. Interestingly, LPS modulated genes related to TGFβ and HSC activation in a manner that would limit their activation and fibrogenic activity. The data indicate that LPS-stimulated HSCs become a major cell type in regulating hepatic inflammatory and immunological responses by altering expression of numerous relevant genes, and thus play a prominent role in hepatic pathophysiology including liver diseases and transplantation.
authors.affiliation: Department of Opthalmology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Stephen A K
authors.initials: SA
authors.lastname: Harvey
authors.affiliation: Department of Surgery, University of Cincinnati, Cincinnati, Ohio, United States of America ; Cincinnati VA Medical Center, Cincinnati, Ohio, United States of America.
authors.forename: Anil
authors.initials: A
authors.lastname: Dangi
authors.affiliation: Department of Surgery, University of Cincinnati, Cincinnati, Ohio, United States of America.
authors.forename: Ashish
authors.initials: A
authors.lastname: Tandon
authors.affiliation: Department of Surgery, University of Cincinnati, Cincinnati, Ohio, United States of America ; Cincinnati VA Medical Center, Cincinnati, Ohio, United States of America ; Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.
authors.forename: Chandrashekhar R
authors.initials: CR
authors.lastname: Gandhi
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000187:drug effects / Q000235:genetics; D018925:Chemokines / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000201:enzymology / Q000276:immunology* / Q000473:pathology*; D007249:Inflammation / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008099:Liver / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020218:Response Elements / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D051193:Toll-Like Receptors / Q000235:genetics / Q000378:metabolism; D059467:Transcriptome / Q000235:genetics*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism
chemical_list: D018925:Chemokines; D008070:Lipopolysaccharides; D016328:NF-kappa B; D012333:RNA, Messenger; D051193:Toll-Like Receptors; D016212:Transforming Growth Factor beta; D020928:Mitogen-Activated Protein Kinases