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Differential Production of IL-23 and IL-12 by Myeloid-Derived Dendritic Cells in Response to TLR Agonists¹

Robert E. Roses^2,*, Shuwen Xu^2,*, Min Xu^*, Ursula Koldovsky^*, Gary Koski and Brian J. Czerniecki^3,*

^* Harrison Department of Surgical Research and Department of Surgery, University of Pennsylvania, Philadelphia, PA 19104; and Center for Surgery Research, Cleveland Clinic Foundation, Cleveland, OH 44195

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- 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This study was supported by the National Institutes of Health (R01-CA096997-02) and the American Cancer Society (RSG 99-029-04-LIB).

² R.E.R. and S.X. contributed equally to the preparation of this manuscript.

³ Address correspondence and reprint requests to Dr. Brian J. Czerniecki, Department of Surgery, 4 Silverstein, 3400 Spruce Street, Philadelphia, PA 19104. E-mail address: brian.czerniecki{at}uphs.upenn.edu

⁴ Abbreviations used in this paper: DC, dendritic cell; LTA, lipotechoic acid; SFM, serum-free medium; iDC, immature DC.