title: TLR-2 is upregulated and mobilized to the hepatocyte plasma membrane in the space of Disse and to the Kupffer cells TLR-4 dependently during acute endotoxemia in mice.
abstract: Membrane components of bacteria and fungi are recognized by Toll-like receptors (TLRs) which, when activated, induce several inflammatory mediators important in the host defense. As the liver is constantly exposed to ingested bacteria, hepatic TLRs must be broadly responsive and highly regulated to prevent uncontrolled inflammatory activation. Although several hepatic cells express microbe recognition molecules and inflammatory mediators in vitro, the regulation and cellular localization of these proteins in vivo remain uncertain. The expression and regulation of TLR-2 and TLR-4, and the cytokine expression patterns were evaluated in mouse tissues using a model of acute inflammation induced by intraperitoneal injection of LPS. Five hours after intraperitoneal LPS, induction of TLR-4 was evident in lung, while the low hepatic TLR-4 expression was non-inducible. TLR-2 mRNA and protein were induced both in lung and liver TLR-4 dependently. However, IL-1alpha also contributed to this induction, and IL-1R1 antibody attenuated the TLR-2 increase. Immunoelectron microscopy showed accumulation of cytoplasmic TLR-2 to vesicles near the hepatocyte plasma membrane in the space of Disse, to the sinusoidal endothelium and to the Kupffer cells. NF-kappaB activation was clear in Kupffer cells and hepatocytes during LPS-challenge, suggesting these cells to be the main source of in vivo cytokine production. Hepatic cytokine response to LPS was remarkably rapid in liver, whereas lung responded less acutely. Secondary inflammatory challenge attenuated the TLR-2 response. The innate immune system of the liver is rapidly and transiently activated during endotoxemia by mechanism involving both TLR-4 and TLR-2.
authors.affiliation: Department of Pediatrics, Biocenter Oulu, P.O. Box 5000, FIN-90014 University of Oulu, Oulu, Finland. marja.ojaniemi@oulu.fi
authors.forename: Marja
authors.initials: M
authors.lastname: Ojaniemi
authors.forename: Mari
authors.initials: M
authors.lastname: Liljeroos
authors.forename: Kirsi
authors.initials: K
authors.lastname: Harju
authors.forename: Raija
authors.initials: R
authors.lastname: Sormunen
authors.forename: Reetta
authors.initials: R
authors.lastname: Vuolteenaho
authors.forename: Mikko
authors.initials: M
authors.lastname: Hallman
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D019446:Endotoxemia / Q000276:immunology*; D022781:Hepatocytes / Q000378:metabolism / Q000648:ultrastructure; D007249:Inflammation / Q000276:immunology; D007728:Kupffer Cells / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008099:Liver / Q000378:metabolism*; D008168:Lung / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D015846:Monokines / Q000502:physiology; D016328:NF-kappa B / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000235:genetics* / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D008070:Lipopolysaccharides; D015846:Monokines; D016328:NF-kappa B; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4