title: TLR Signalling Pathways Diverge in Their Ability to Induce PGE2.
abstract: PGE2 is a lipid mediator abundantly produced in inflamed tissues that exerts relevant immunoregulatory functions. Dendritic cells (DCs) are key players in the onset and shaping of the inflammatory and immune responses and, as such, are well known PGE2 targets. By contrast, the precise role of human DCs in the production of PGE2 is poorly characterized. Here, we asked whether different ligands of Toll-like receptors (TLRs), a relevant family of pathogen-sensing receptors, could induce PGE2 in human DCs. The only active ligands were LPS (TLR4 ligand) and R848 (TLR7-8 ligand) although all TLRs, but TLR9, were expressed and functional. While investigating the molecular mechanisms hindering the release of PGE2, our experiments highlighted so far oversight differences in TLR signalling pathways in terms of MAPK and NF-κB activation. In addition, we identified that the PGE2-limiting checkpoint downstream TLR3, TLR5, and TLR7 was a defect in COX2 induction, while TLR1/2 and TLR2/6 failed to mobilize arachidonic acid, the substrate for the COX2 enzyme. Finally, we demonstrated the in vivo expression of PGE2 by myeloid CD11c(+) cells, documenting a role for DCs in the production of PGE2 in human inflamed tissues.
authors.affiliation: Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy.
authors.forename: Valentina
authors.identifier: 0000-0003-4802-1524
authors.initials: V
authors.lastname: Salvi
authors.affiliation: Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy.
authors.forename: Xenia
authors.initials: X
authors.lastname: Vaira
authors.affiliation: Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy.
authors.forename: Veronica
authors.initials: V
authors.lastname: Gianello
authors.affiliation: Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy.
authors.forename: William
authors.initials: W
authors.lastname: Vermi
authors.affiliation: Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy.
authors.forename: Mattia
authors.initials: M
authors.lastname: Bugatti
authors.affiliation: Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy; Humanitas Clinical and Research Center, 20089 Rozzano, Italy.
authors.forename: Silvano
authors.initials: S
authors.lastname: Sozzani
authors.affiliation: Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy.
authors.forename: Daniela
authors.identifier: 0000-0001-6276-5365
authors.initials: D
authors.lastname: Bosisio
mesh_terms: D015153:Blotting, Western; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism*; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007150:Immunohistochemistry; D016209:Interleukin-8 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D060888:Real-Time Polymerase Chain Reaction; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D051199:Toll-Like Receptor 7 / Q000378:metabolism*; D051200:Toll-Like Receptor 8 / Q000378:metabolism*
chemical_list: D007093:Imidazoles; D016209:Interleukin-8; D008070:Lipopolysaccharides; D051197:Toll-Like Receptor 4; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D015232:Dinoprostone; C402365:resiquimod