Diterpenes inhibit IL-12 production by DC and enhance Th2 cells polarization

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Abstract

Sugiol and 12-hydroxy-6,7-secoabieta-8,11,13-triene-6,7-dial (Secoferruginol) are diterpenes isolated from the heartwood of Cryptomeria japonica and are pharmacologically active substances. Dendritic cells (DC) have a key influence on the differentiation of naïve T cells into Th1 or Th2 effector cells. We demonstrate that Sugiol and Secoferruginol activate human DC as documented by phenotypic and functional maturation and altered cytokine production. Human monocytes were exposed to Sugiol or Secoferruginol alone, or in combination with LPS and thereafter co-cultured with naïve T cells. The expression levels of CD83 on Sugiol-primed DC were enhanced. Sugiol dose-dependently inhibited IL-12p70 production by LPS-primed DC and to a lesser extent, the production of the proinflammatory cytokines. Naïve T cells co-cultured with Sugiol-primed DC, turned into typical Th2 which produced large quantities of IL-4 and released small amounts of IFN-γ and reduced Th1 cell polarizing capacity. Sugiol-primed DC induced the development of Th2 cells via the enhanced expression of OX40L and augmented the Th2 cell polarizing capacity of DC via the inhibition of IL-12p70. Similar results were obtained with Secoferruginol. These results suggest that some diterpenes modulate human DC function in a fashion that favors Th2 cell polarization and might have implication in autoimmune diseases.

Section snippets

Materials and methods

Culture medium, reagents, and monoclonal antibodies. The culture medium used in this study was serum-free AIM-V medium (Life Technologies, Paislex, UK). Recombinant human IL-4 (IL-4), recombinant human granulocyte-macrophage colony-stimulation factor (GM-CSF), CD40-L, rhIL-10, anti-IL10 mAb, rhIL-12, and anti-OX40L mAb were purchased from R&D Systems (Minneapolis, MN). LPS from Escherichia coli were purchased from Sigma–Aldrich (St. Louis, MO). For flow cytometry, monoclonal antibodies (mAbs)

Results and discussion

To investigate the direct effects of Sugiol or Secoferruginol on the function of human DC, immature monocyte-derived DC were exposed to Sugiol or Secoferruginol, and phenotypical and functional DC maturation were analyzed. Human monocytes were cultured with GM-CSF and IL-4 for 6 days under standard conditions, followed by another 2 days in the presence of various concentrations of Sugiol or Secoferruginol. The expression levels of CD1a, CD80, CD86, and HLA-DR as expressed by MFI on Sugiol- or

Acknowledgment

We thank Mrs. Annette Wallisch for critical reading of the manuscript.

References (31)

  • V.K. Kuchroo et al.

    B7-1 and B7-2 costimulatory molecules activate differentially the Th1/Th2 development pathways: application to autoimmune disease therapy

    Cell

    (1995)
  • J.A. Lederer et al.

    Cytokine transcriptional events during helper T cell subset differentiation

    J. Exp. Med.

    (1996)
  • X. Tao et al.

    Induction of IL-4-producing CD4+ T cells by antigenic peptides altered for TCR binding

    J. Immunol.

    (1997)
  • G. Iezzi et al.

    The interplay between the duration of TCR and cytokine signaling determines T cell polarization

    Eur. J. Immunol.

    (1997)
  • H. Tanaka et al.

    Human monocyte-derived dendritic cells induce naïve T cell differentiation into T helper cell type 2 (Th2) or TH1/Th2 effectors: role of stimulator/responder ratio

    J. Exp. Med.

    (2000)
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