title: Hepatic stellate cells primed with cytokines upregulate inflammation in response to peptidoglycan or lipoteichoic acid.
abstract: Gram-positive bacterial products such as peptidoglycan (PGN) and lipoteichoic acid (LTA) are potent stimulators of innate inflammatory responses. We previously reported that lipopolysaccharide (LPS), a major biologically active agent of gram-negative bacteria, induces a proinflammatory response via the Toll-like receptor (TLR) 4 in hepatic stellate cells (HSCs). Here we investigated the mechanism of proinflammatory action by PGN and LTA in activated human HSCs. Following treatment with either TNF-alpha or IL-1beta, expression of TLR2 and CD14 was determined by real-time PCR and Western blotting. NF-kappaB activation was assessed by NF-kappaB-driven luciferase assay and electrophoretic mobility shift assay. Interleukin-8 (IL-8) from culture supernatant was measured by ELISA. Activated human HSCs express TLR2 and CD14, which are receptors for PGN and LTA signaling. TNF-alpha and IL-1beta significantly upregulated the expression of TLR2 mRNA and protein in HSCs. PGN and LTA induced NF-kappaB activation and stimulated production of IL-8 in HSCs. Pretreatment with TNF-alpha or IL-1beta augmented NF-kappaB activation and IL-8 production in response to PGN or LTA. Both PGN- and LTA-induced NF-kappaB activation and IL-8 secretion were completely inhibited by anti-TLR2 blocking antibody (T2.5). These findings suggest that TNF-alpha or IL-1beta primed HSCs enhance the production of IL-8 in response to PGN and LTA through augmentation of the TLR2 system.
authors.affiliation: Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, South Korea.
authors.forename: Yong-Han
authors.initials: YH
authors.lastname: Paik
authors.forename: Kwan Sik
authors.initials: KS
authors.lastname: Lee
authors.forename: Hyun Jin
authors.initials: HJ
authors.lastname: Lee
authors.forename: Kyung Min
authors.initials: KM
authors.lastname: Yang
authors.forename: Se Jun
authors.initials: SJ
authors.lastname: Lee
authors.forename: Dong Ki
authors.initials: DK
authors.lastname: Lee
authors.forename: Kwang-Hyub
authors.initials: KH
authors.lastname: Han
authors.forename: Chae Yoon
authors.initials: CY
authors.lastname: Chon
authors.forename: Sang In
authors.initials: SI
authors.lastname: Lee
authors.forename: Young Myoung
authors.initials: YM
authors.lastname: Moon
authors.forename: David A
authors.initials: DA
authors.lastname: Brenner
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D015415:Biomarkers / Q000378:metabolism; D018929:Cell Culture Techniques; D002461:Cell Line, Transformed; D016207:Cytokines / Q000276:immunology*; D005355:Fibrosis / Q000139:chemically induced / Q000473:pathology; D017930:Genes, Reporter; D022781:Hepatocytes / Q000166:cytology / Q000502:physiology*; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000473:pathology; D007375:Interleukin-1 / Q000276:immunology; D016209:Interleukin-8 / Q000096:biosynthesis; D018950:Lipopolysaccharide Receptors / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology*; D008099:Liver / Q000166:cytology*; D008156:Luciferases / Q000276:immunology; D016328:NF-kappa B / Q000276:immunology; D010457:Peptidoglycan / Q000276:immunology*; D013682:Teichoic Acids / Q000276:immunology*; D051195:Toll-Like Receptor 2 / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology; D015854:Up-Regulation / Q000276:immunology
chemical_list: D015415:Biomarkers; D016207:Cytokines; D007375:Interleukin-1; D016209:Interleukin-8; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D016328:NF-kappa B; D010457:Peptidoglycan; D013682:Teichoic Acids; D051195:Toll-Like Receptor 2; D014409:Tumor Necrosis Factor-alpha; C009900:lipoteichoic acid; D008156:Luciferases