title: TLR ligands, but not modulators of histone modifiers, can induce the complex immune response pattern of endotoxin tolerance in mammary epithelial cells.
abstract: Excessive stimulation of the TLR4 axis through LPS reduces the expression of some cytokine genes in immune cells, while stimulating the expression of immune defense genes during a subsequent bacterial infection. This endotoxin tolerance (ET) is mediated via epigenetic mechanisms. Priming the udder of cows with LPS was shown to induce ET in mammary epithelial cells (MEC), thereby protecting the udder against reinfection for some time. Seeking alternatives to LPS priming we tried to elicit ET by priming MEC with either lipopeptide (Pam2CSK4) via the TLR2/6 axis or inhibitors of histone-modifying enzymes. Pre-incubation of MEC with Pam2CSK4 enhanced baseline and induced expression of bactericidal (β-defensin; SLPI) and membrane protecting factors ( SAA3, TGM3), while reducing the expression of cytokine- and chemokine-encoding genes ( TNF, IL1β) after a subsequent pathogen challenge, the latter, however, not as efficiently as after LPS priming. Pre-treating MEC with various inhibitors of histone H3 modifiers (for demethylation, acetylation or deacetylation) all failed to induce any of the protective factors and only resulted in some dampening of cytokine gene expression after the re-challenge. Hence, triggering immune functions via the TLR axis, but not through those histone modifiers, induced the beneficial phenomenon of ET in MEC.
authors.affiliation: 1 Leibniz Institute for Farm Animal Biology, Institute for Genome Biology, Dummerstorf, Germany.
authors.forename: Juliane
authors.initials: J
authors.lastname: Günther
authors.affiliation: 2 Clinic for Ruminants with Ambulance and Herd Health Services, Centre for Clinical Veterinary Medicine, LMU Munich, Munich, Germany.
authors.forename: Wolfram
authors.initials: W
authors.lastname: Petzl
authors.affiliation: 2 Clinic for Ruminants with Ambulance and Herd Health Services, Centre for Clinical Veterinary Medicine, LMU Munich, Munich, Germany.
authors.forename: Holm
authors.initials: H
authors.lastname: Zerbe
authors.affiliation: 3 Immunology Unit, University of Veterinary Medicine Foundation, Hannover, Germany.
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Schuberth
authors.affiliation: 1 Leibniz Institute for Farm Animal Biology, Institute for Genome Biology, Dummerstorf, Germany.
authors.forename: Hans-Martin
authors.initials: HM
authors.lastname: Seyfert
mesh_terms: D000818:Animals; D001424:Bacterial Infections / Q000276:immunology*; D002417:Cattle; D002478:Cells, Cultured; D044127:Epigenesis, Genetic; D005260:Female; D006657:Histones / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D055666:Lipopeptides / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000276:immunology; D008321:Mammary Glands, Animal / Q000187:drug effects* / Q000276:immunology; D008414:Mastitis, Bovine / Q000276:immunology*; D053481:Secretory Leukocyte Peptidase Inhibitor / Q000235:genetics / Q000378:metabolism; D000685:Serum Amyloid A Protein / Q000235:genetics / Q000378:metabolism; D012772:Shock, Septic / Q000276:immunology* / Q000517:prevention & control; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D011503:Transglutaminases / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D023083:beta-Defensins / Q000235:genetics / Q000378:metabolism
chemical_list: D006657:Histones; D053583:Interleukin-1beta; D055666:Lipopeptides; D008070:Lipopolysaccharides; C560312:Pam2CSK4 lipopeptide; D053481:Secretory Leukocyte Peptidase Inhibitor; D000685:Serum Amyloid A Protein; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D023083:beta-Defensins; D011503:Transglutaminases
keywords: Endotoxin tolerance; epigenetic mechanisms; immune modulation; mammary epithelial cells; mastitis