title: Endotoxin modulates the capacity of CpG-activated liver myeloid DC to direct Th1-type responses.
abstract: DC are believed to play important roles in the induction and regulation of immune responses in the liver, an organ implicated in peripheral tolerance. Since the liver is located downstream of the gut, it is constantly exposed to bacterial LPS. Our recent observations indicate that prior exposure to endotoxin modulates subsequent liver DC responses to this TLR4 ligand. In this study, we demonstrate that endotoxin modifies the capacity of mouse liver myeloid DC (MDC) activated by CpG (TLR9 ligand) to direct Th1-type responses. IL-12 production by liver MDC was significantly lower than that of spleen MDC following CpG or Imiquimod (R837; TLR7 ligand) activation in vitro. In addition, allogeneic T cells stimulated by CpG-activated liver MDC secreted significantly lower levels of IFN-gamma than T cells stimulated with CpG-activated spleen MDC. A similar effect on liver DC was observed in response to in vivo CpG administration. This effect may be explained by exposure of the DC to endotoxin, because LPS attenuated IL-12 production by CpG-stimulated liver MDC, both in vitro and in vivo. Moreover, attenuation of the response to CpG was not observed in liver MDC from TLR4-mutant (C3H/HeJ) mice, in which TLR4 signaling is impaired. These data suggest that endotoxin-induced 'cross-tolerance' to TLR ligands in liver DC may contribute to down-regulation of hepatic immune responses.
authors.affiliation: Thomas E. Starzl Transplantation Institute and Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA.
authors.forename: Masanori
authors.initials: M
authors.lastname: Abe
authors.forename: Daisuke
authors.initials: D
authors.lastname: Tokita
authors.forename: Giorgio
authors.initials: G
authors.lastname: Raimondi
authors.forename: Angus W
authors.initials: AW
authors.lastname: Thomson
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000634:Aminoquinolines / Q000494:pharmacology; D000818:Animals; D039521:CD11c Antigen / Q000276:immunology / Q000378:metabolism; D018899:CpG Islands / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology*; D004731:Endotoxins / Q000276:immunology*; D005434:Flow Cytometry; D000077271:Imiquimod; D007108:Immune Tolerance; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D018664:Interleukin-12 / Q000096:biosynthesis / Q000276:immunology; D008099:Liver / Q000166:cytology / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D008562:Membrane Glycoproteins / Q000187:drug effects; D051379:Mice; D013154:Spleen / Q000166:cytology / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology*; D051199:Toll-Like Receptor 7 / Q000187:drug effects; D051217:Toll-Like Receptor 9 / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D000634:Aminoquinolines; D039521:CD11c Antigen; D004731:Endotoxins; D008562:Membrane Glycoproteins; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9; D018664:Interleukin-12; D007371:Interferon-gamma; D000077271:Imiquimod