title: Trichuris suis soluble products induce Rab7b expression and limit TLR4 responses in human dendritic cells.
abstract: Inflammatory immune disorders such as inflammatory bowel disease and multiple sclerosis are major health problems. Currently, the intestinal whipworm Trichuris suis is being explored in clinical trials to reduce inflammation in these diseases; however, the mechanisms by which the parasite affects the host immune system are not known. Here we determined the effects of T. suis soluble products (SPs) on Toll-like receptor-4 (TLR4)-stimulated human dendritic cells (DCs) using Illumina bead chip gene arrays. Pathway analysis of lipopolysaccharide-stimulated DCs with or without T. suis treatment showed that co-stimulation with T. suis SPs resulted in a downregulation of both the myeloid differentiation primary response gene 88-dependent and the TIR-domain-containing adaptor-inducing interferon-β-dependent signalling pathways triggered by TLR4. These data were verified using quantitative real-time PCR of several key genes within these pathways and/or defining their protein levels. In addition, T. suis SPs induce Rab7b, a negative regulator of TLR4 signalling that interferes with its trafficking, which coincided with a reduced surface expression of TLR4. These data indicate that the mechanism by which T. suis SPs reduce inflammatory responses is through suppression of both TLR4 signalling and surface expression on DCs.
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: E J
authors.initials: EJ
authors.lastname: Klaver
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: T C T M
authors.initials: TC
authors.lastname: van der Pouw Kraan
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: L C
authors.initials: LC
authors.lastname: Laan
authors.affiliation: Section for Parasitology, Health and Development, Department of Veterinary Disease Biology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: H
authors.initials: H
authors.lastname: Kringel
authors.affiliation: Department of Biochemistry, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: R D
authors.initials: RD
authors.lastname: Cummings
authors.affiliation: Department of Gastroenterology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: G
authors.initials: G
authors.lastname: Bouma
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: G
authors.initials: G
authors.lastname: Kraal
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: I
authors.initials: I
authors.lastname: van Die
mesh_terms: D000818:Animals; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000469:parasitology*; D015536:Down-Regulation; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000469:parasitology / Q000628:therapy; D008070:Lipopolysaccharides / Q000494:pharmacology; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D059467:Transcriptome; D014258:Trichuris / Q000276:immunology*; D020691:rab GTP-Binding Proteins / Q000378:metabolism*; D000090802:rab7 GTP-Binding Proteins
chemical_list: D008070:Lipopolysaccharides; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D000090802:rab7 GTP-Binding Proteins; D020691:rab GTP-Binding Proteins