title: Engagement of Toll-like receptor 2 enhances interleukin (IL)-17(+) autoreactive T cell responses via p38 mitogen-activated protein kinase signalling in dendritic cells.
abstract: Functional analysis of single Toll-like receptors (TLRs) in vivo is necessary to understand how they shape the ocular inflammation involved in uveitis. In this study we explored the role and mechanisms of TLR-2 agonists on the autoreactive T helper type 17 (Th17) response in experimental autoimmune uveitis (EAU). Treatment by peptidoglycan (PGN), a specific TLR-2 agonist, remarkably increased mRNA levels of Th17-lineage genes interleukin (IL)-17A, IL-21 and RAR-related orphan receptor (ROR)γt and promoted antigen-specific Th17 response in EAU mice. A mixture of PGN and interphotoreceptor retinoid-binding protein peptide (IRBP161-180 ) could effectively induce EAU in the absence of complete Freund's adjuvant (CFA). PGN treatment also enhanced the pathogenic activities of activated antigen-specific Th17 cells in vivo. PGN significantly increased the production of IL-1β, IL-6 and IL-23 of dendritic cells (DCs) and enhanced their ability to promote IL-17(+) uveitogenic T cells. Enhanced immunostimulatory activities of PGN-DCs depend upon p38 activation. Inhibition of p38 mitogen-activated protein kinase (MAPK) activity dramatically decreased IL-17 gene expression and antigen-specific Th17 responses stimulated by PGN-DCs. Our findings suggest that PGN treatment dramatically promotes the IL-17(+) uveitogenic T cell responses via enhancing the immunostimulatory activities of DCs. This effect may be mediated, at least in part, by activation of the p38 signalling pathway in DCs.
authors: Tianjin Medical University Eye Hospital and Eye Institute, Tianjin, China.
authors: R
authors: R
authors: Wei
authors: L
authors: L
authors: Dong
authors: Q
authors: Q
authors: Xiao
authors: D
authors: D
authors: Sun
authors: X
authors: X
authors: Li
authors: H
authors: H
authors: Nian
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015551:Autoimmunity; D019070:Cell Lineage / Q000235:genetics; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D018836:Inflammation Mediators / Q000378:metabolism; D051379:Mice; D010457:Peptidoglycan / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D058504:Th17 Cells / Q000276:immunology* / Q000378:metabolism*; D051195:Toll-Like Receptor 2 / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D018836:Inflammation Mediators; D010457:Peptidoglycan; D012333:RNA, Messenger; D051195:Toll-Like Receptor 2; D048051:p38 Mitogen-Activated Protein Kinases
keywords: DCs; EAU; Th17 cells; p38 MAPK