title: Differential production of IL-23 and IL-12 by myeloid-derived dendritic cells in response to TLR agonists.
abstract: The recently delineated role for IL-23 in enhancing Th-17 activity suggests that regulation of its expression is distinct from that of IL-12. We hypothesized that independent TLR-mediated pathways are involved in the regulation of IL-12 and IL-23 production by myeloid-derived dendritic cells (DCs). The TLR 2 ligand, lipoteichoic acid (LTA), the TLR 4 ligand, LPS, and the TLR 7/8 ligand, resimiquod (R848), induced production of IL-23 by DCs. None of these TLR ligands alone induced significant IL-12 production, except when combined with IFN-gamma or other TLR ligands. Notably, IL-23 production in response to single TLR ligands was inhibited by IL-4. DCs treated with single TLR agonists induced IL-17A production by allogeneic and Ag-specific memory CD4(+) T cells, an effect that was abrogated by IL-23 neutralization. Moreover, these DCs stimulated IL-17A production by tumor peptide-specific CD8(+) T cells. In contrast, DCs treated with dual signals induced naive and memory Th1 responses and enhanced the functional avidity of tumor-specific CD8(+) T cells. These results indicate that distinct microbial-derived stimuli are required to drive myeloid DC commitment to IL-12 or IL-23 production, thereby differentially polarizing T cell responses.
authors.affiliation: Harrison Department of Surgical Research and Department of Surgery, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Roses
authors.forename: Shuwen
authors.initials: S
authors.lastname: Xu
authors.forename: Min
authors.initials: M
authors.lastname: Xu
authors.forename: Ursula
authors.initials: U
authors.lastname: Koldovsky
authors.forename: Gary
authors.initials: G
authors.lastname: Koski
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Czerniecki
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007371:Interferon-gamma / Q000096:biosynthesis / Q000494:pharmacology; D018664:Interleukin-12 / Q000096:biosynthesis*; D020381:Interleukin-17 / Q000096:biosynthesis; D053759:Interleukin-23 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D008024:Ligands; D008070:Lipopolysaccharides / Q000494:pharmacology; D022423:Myeloid Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D013682:Teichoic Acids / Q000494:pharmacology; D051193:Toll-Like Receptors / Q000819:agonists*
chemical_list: D007093:Imidazoles; D020381:Interleukin-17; D053759:Interleukin-23; D008024:Ligands; D008070:Lipopolysaccharides; D013682:Teichoic Acids; D051193:Toll-Like Receptors; D018664:Interleukin-12; C009900:lipoteichoic acid; D007371:Interferon-gamma; C402365:resiquimod