title: Toll-like receptor-induced innate immune responses in non-parenchymal liver cells are cell type-specific.
abstract: Little is known of how the Toll-like receptor (TLR) system can modulate the function of non-parenchymal liver cells (NPC) as a major component of the innate and adaptive immune system of the liver. To investigate the diversification of TLR signalling pathways in NPC, we isolated Kupffer cells (KC) and liver sinusoidal endothelial cells (LSEC) from wild-type C57BL/6 mice and examined their responses to TLR1 to TLR9 agonists. The data show that KC respond to all TLR ligands by producing tumour necrosis factor-alpha (TNF-alpha) or interleukin-6 (IL-6), to TLR3 and TLR4 ligands only by producing interferon-beta (IFN-beta), to TLR1 and TLR8 ligands by significantly up-regulating major histocompatibility complex (MHC) class II and costimulatory molecules, and to TLR1, -2, -4 and -6 ligands by inducing high levels of T-cell proliferation and IFN-gamma production in the mixed lymphocyte reaction (MLR). Similarly, LSEC respond to TLR1 to -4, -6, -8 and -9 ligands by producing TNF-alpha, to TLR3 and -4 ligands by producing IL-6, and to TLR3 ligands by producing IFN-beta. Interestingly, despite significant up-regulation of MHC class II and co-stimulatory molecules in response to TLR8 ligands, LSEC stimulated by TLR1, -2 or -6 could stimulate allogeneic T cells as assessed by MLR. By contrast, myeloid dendritic cells, used as positive control for classical antigen-presenting cells, respond to TLR1, -2, -4 and -9 ligands by both up-regulation of CD40 and activation of allogeneic T cells. In conclusion, NPC display a restricted TLR-mediated activation profile when compared with 'classical' antigen-presenting cells which may, at least in part, explain their tolerogenic function in the liver.
authors.affiliation: Department of Gastroenterology and Hepatology, University Hospital of Essen, University Duisburg-Essen, Essen, Germany. junwu@tjh.tjmu.edu.cn
authors.forename: Jun
authors.initials: J
authors.lastname: Wu
authors.forename: Zhongji
authors.initials: Z
authors.lastname: Meng
authors.forename: Min
authors.initials: M
authors.lastname: Jiang
authors.forename: Ejuan
authors.initials: E
authors.lastname: Zhang
authors.forename: Martin
authors.initials: M
authors.lastname: Trippler
authors.forename: Ruth
authors.initials: R
authors.lastname: Broering
authors.forename: Agnes
authors.initials: A
authors.lastname: Bucchi
authors.forename: Frank
authors.initials: F
authors.lastname: Krux
authors.forename: Ulf
authors.initials: U
authors.lastname: Dittmer
authors.forename: Dongliang
authors.initials: D
authors.lastname: Yang
authors.forename: Michael
authors.initials: M
authors.lastname: Roggendorf
authors.forename: Guido
authors.initials: G
authors.lastname: Gerken
authors.forename: Mengji
authors.initials: M
authors.lastname: Lu
authors.forename: Joerg F
authors.initials: JF
authors.lastname: Schlaak
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D015703:Antigens, CD / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D017077:Culture Media, Conditioned / Q000494:pharmacology; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D004686:Encephalomyocarditis virus / Q000276:immunology; D042783:Endothelial Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D015870:Gene Expression / Q000235:genetics / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D007113:Immunity, Innate / Q000276:immunology*; D016898:Interferon-alpha / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D016899:Interferon-beta / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D015850:Interleukin-6 / Q000378:metabolism; D007728:Kupffer Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D008099:Liver / Q000166:cytology* / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D011070:Poly I-C / Q000494:pharmacology; D013601:T-Lymphocytes / Q000276:immunology; D051196:Toll-Like Receptor 3 / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D051193:Toll-Like Receptors / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects / Q000276:immunology
chemical_list: D000906:Antibodies; D015703:Antigens, CD; D017077:Culture Media, Conditioned; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D016898:Interferon-alpha; D015850:Interleukin-6; C519703:TLR3 protein, mouse; C493487:Tlr4 protein, mouse; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D016899:Interferon-beta; D011070:Poly I-C