title: Stimulation of mast cells via FcvarepsilonR1 and TLR2: the type of ligand determines the outcome.
abstract: Little is known about the interplay between pathophysiological processes of allergy and infection, particularly with respect to mast cell (MC)-mediated responses. The presence and recognition of pathogen-associated molecular patterns (PAMPs) might have broad impact on the development and severity of diseases. In this study, we assessed the influence of toll-like receptor 2 (TLR 2)-dependent synthetic analogs of bacterial lipopeptides (LPs), Pam(3)CSK(4) and MALP-2, on Ag (DNP-HSA)-triggered responses in bone marrow-derived MCs (BMMCs). Both LPs strongly synergized with sub-optimal amounts of Ag in the stimulation of cytokine release. Intriguingly, Pam(3)CSK(4), but not MALP-2 suppressed Ag-induced degranulation of BMMCs (together with early tyrosine phosphorylation and calcium mobilization) in a TLR2-independent manner. Further analysis revealed that Pam(3)CSK(4), most probably by electrostatic forces, reduced the level of active DNP-HSA and that this, in turn, was responsible for the suppression of Ag-induced degranulation. Thus, our work demonstrates that LPs can synergize with IgE+Ag in stimulating the production of IL-6 by BMMCs. As well, our findings with Pam(3)CSK(4) indicate that one must be cautious when interpretating results obtained with "model" substances and the combination of ligands must be carefully chosen when functional interactions between the high-affinity receptor for IgE (FcepsilonR1) and TLR2 are examined.
authors.affiliation: Department of Molecular Immunology, Biology III, University of Freiburg, Stübeweg 51, 79108 Freiburg, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Fehrenbach
authors.forename: Fillip
authors.initials: F
authors.lastname: Port
authors.forename: Gordon
authors.initials: G
authors.lastname: Grochowy
authors.forename: Christoph
authors.initials: C
authors.lastname: Kalis
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Bessler
authors.forename: Chris
authors.initials: C
authors.lastname: Galanos
authors.forename: Gerald
authors.initials: G
authors.lastname: Krystal
authors.forename: Marina
authors.initials: M
authors.lastname: Freudenberg
authors.forename: Michael
authors.initials: M
authors.lastname: Huber
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000819:agonists / Q000276:immunology / Q000494:pharmacology*; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology; D020013:Calcium Signaling / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology; D004357:Drug Synergism; D006967:Hypersensitivity / Q000276:immunology; D007073:Immunoglobulin E / Q000276:immunology / Q000494:pharmacology*; D007239:Infections / Q000276:immunology; D008024:Ligands; D008297:Male; D008407:Mast Cells / Q000166:cytology / Q000276:immunology*; D051379:Mice; D018448:Models, Immunological; D009842:Oligopeptides / Q000819:agonists / Q000276:immunology / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D017455:Receptors, IgE / Q000819:agonists* / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000819:agonists* / Q000276:immunology
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D016207:Cytokines; D008024:Ligands; D009842:Oligopeptides; D017455:Receptors, IgE; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D007073:Immunoglobulin E