title: TLR10 Is a Negative Regulator of Both MyD88-Dependent and -Independent TLR Signaling.
abstract: TLRs are central components of the innate immune system which, upon recognition of bacterial, fungal or viral components, activate intracellular signals that lead to protective inflammatory responses. Among the 10-member human TLR family, TLR10 is the only remaining orphan receptor without a known ligand or signaling function. Murine TLR10 is a disrupted pseudogene, which precludes investigation using classic gene knockout approaches. We report here that TLR10 suppressed the production of an array of cytokines in stably transfected human myelomonocytic U937 cells in response to other TLR agonists. This broad TLR suppressive activity affects both MyD88- and TRIF-inducing IFN-β-mediated signaling pathways upstream of IκB and MAPK activation. Compared with nontransgenic littermate controls, monocytes of TLR10 transgenic mice exhibited blunted IL-6 production following ex vivo blood stimulation with other TLR agonists. After i.p. injection of LPS, lower levels of TNFα, IL-6, and type 1 IFN were measured in the serum of TLR10 transgenic mice compared to nontransgenic mice, but did not affect mouse survival in an LPS-induced septic shock model. Finally, treatment of human mononuclear cells with a monoclonal anti-TLR10 Ab suppressed proinflammatory cytokines released by LPS stimulation. These results demonstrate that TLR10 functions as a broad negative regulator of TLR signaling and suggests that TLR10 has a role in controlling immune responses in vivo.
authors.affiliation: Department of Microbiology, University of Illinois at Urbana-Champaign, Urbana, IL 61801; and College of Medicine, University of Illinois at Urbana-Champaign, Urbana, IL 61801.
authors.forename: Song
authors.initials: S
authors.lastname: Jiang
authors.affiliation: Department of Microbiology, University of Illinois at Urbana-Champaign, Urbana, IL 61801; and.
authors.forename: Xinyan
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Microbiology, University of Illinois at Urbana-Champaign, Urbana, IL 61801; and.
authors.forename: Nicholas J
authors.identifier: 0000-0001-5720-9305
authors.initials: NJ
authors.lastname: Hess
authors.affiliation: Department of Microbiology, University of Illinois at Urbana-Champaign, Urbana, IL 61801; and.
authors.forename: Yue
authors.initials: Y
authors.lastname: Guan
authors.affiliation: Department of Microbiology, University of Illinois at Urbana-Champaign, Urbana, IL 61801; and College of Medicine, University of Illinois at Urbana-Champaign, Urbana, IL 61801 Tapping@Life.illinois.edu.
authors.forename: Richard I
authors.initials: RI
authors.lastname: Tapping
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism; D000818:Animals; D006801:Humans; D007113:Immunity, Innate; D018836:Inflammation Mediators / Q000378:metabolism; D016899:Interferon-beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000276:immunology*; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism*; D015398:Signal Transduction; D051201:Toll-Like Receptor 10 / Q000235:genetics / Q000378:metabolism*; D019076:Transgenes / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D020298:U937 Cells
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D018836:Inflammation Mediators; D015850:Interleukin-6; D008070:Lipopolysaccharides; D053594:Myeloid Differentiation Factor 88; C470409:TICAM1 protein, human; C475955:TLR10 protein, human; D051201:Toll-Like Receptor 10; D014409:Tumor Necrosis Factor-alpha; D016899:Interferon-beta