title: Toll-like receptor 6 stimulation promotes T-helper 1 and 17 responses in gastrointestinal-associated lymphoid tissue and modulates murine experimental colitis.
abstract: T-helper 1 and 17 (Th1/Th17) responses are important in inflammatory bowel disease (IBD), and research indicates that Toll-like receptor 6 (TLR6) stimulation leads to Th17 cell development within the lung. The gastrointestinal tract, like the lung, is a mucosal surface that is exposed to bacterially derived TLR6 ligands. Thus, we looked at the effects of TLR6 stimulation on the expression of Th17-, Th1-, and regulatory T-cell-associated transcription factors; RORγt, T-bet, and Foxp3, respectively; in CD4+ T cells within gut-associated lymphoid tissue (GALT) in vitro and in vivo. Cells from GALT and spleen were stimulated with anti-CD3 and TLR ligands for TLR1/2 and TLR2/6 (Pam3CSK4 and FSL-1, respectively). FSL-1 was more effective than Pam3CSK4 at inducing Th1 and Th17 responses in the GALT while Pam3CSK4 rivaled FSL-1 in the spleen. TLR6 was further explored in vivo using experimental colitis. Tlr6-/- mice were resistant to colitis, and oral FSL-1 led to more severe colitis in wild-type mice. Similar pro-inflammatory reactions were seen in human peripheral blood mononuclear cells, and TLR6 expression was directly correlated with RORC mRNA levels in inflamed intestines of IBD patients. These results demonstrate that TLR6 supports Th1- and Th17-skewed responses in the GALT and might be an important target for the development of new medical interventions in IBD.
authors.affiliation: Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands.
authors.forename: M E
authors.initials: ME
authors.lastname: Morgan
authors.affiliation: Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands.
authors.forename: P J
authors.initials: PJ
authors.lastname: Koelink
authors.affiliation: Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands.
authors.forename: B
authors.initials: B
authors.lastname: Zheng
authors.affiliation: Tumor Immunology Laboratory, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: M H M G M
authors.initials: MH
authors.lastname: den Brok
authors.affiliation: Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands.
authors.forename: H J G
authors.initials: HJ
authors.lastname: van de Kant
authors.affiliation: Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: H W
authors.initials: HW
authors.lastname: Verspaget
authors.affiliation: Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands.
authors.forename: G
authors.initials: G
authors.lastname: Folkerts
authors.affiliation: Tumor Immunology Laboratory, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: G J
authors.initials: GJ
authors.lastname: Adema
authors.affiliation: Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands.
authors.forename: A D
authors.initials: AD
authors.lastname: Kraneveld
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003092:Colitis / Q000503:physiopathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D005260:Female; D005455:Fluorescent Antibody Technique; D041981:Gastrointestinal Tract / Q000276:immunology*; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D008221:Lymphoid Tissue / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018417:Th1 Cells / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology*; D051216:Toll-Like Receptor 6 / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics
chemical_list: D051216:Toll-Like Receptor 6; D014157:Transcription Factors