Uncarinic acid C plus IFN-γ generates monocyte-derived dendritic cells and induces a potent Th1 polarization with capacity to migrate

Cell Immunol. 2010;266(1):104-10. doi: 10.1016/j.cellimm.2010.09.004. Epub 2010 Sep 18.

Abstract

Uncarinic acid C (URC) is triterpene isolated from Uncaria rhynchophylla and modulates human DC function in a fashion that favors Th1 cell polarization depending on TLR4 signaling. The induction of dendritic cells (DC) is critical for the induction of Ag-specific T lymphocyte responses and may be essential for the development of human vaccines relying on T cell immunity. Monocyte-derived DC used as adjuvant cells in cancer immunotherapy and have shown promising results. We studied the effect of interferon's (IFN-α and IFN-γ) and TNF-α on phenotypic and functional maturation, and cytokine production of URC-primed DC in vitro. Human monocytes were exposed to either URC alone, or in combination with TNF-α, IFN-α or IFN-γ, and thereafter co-cultured with naïve T cells. We found that the expression levels of CD1a, CD83 and HLA-DR on URC-primed DC were influenced by IFN-γ and IFN-γ augmented the T cell stimulatory capacity in allo MLR to URC-primed DC. Moreover, the production of IL-12p70 by URC-primed DC was enhanced by IFN-γ. IL-12p70 production by URC-primed DC alone was influenced following treatment with anti-TLR4 mAb, but not DC differentiated with URC plus IFN-γ. URC plus IFN-γ-primed DC induced a substantial increase in the secretion of IFN-γ by T cells, which is dependent on IL-12 secretion. DC maturated with URC plus IFN-γ had an intermediate migratory capacity towards CCL19 and CCL21. In addition, the expression levels of CCR7 on URC-primed DC were enhanced by IFN-γ. In contrast, surface molecule up-regulation and function of URC-primed DC were slightly enhanced by TNF-α, and IFN-α. These results suggest that the enhancement of Th1 cells polarization to URC-primed DC induced by IFN-γ depends on the activation of IL-12p70 and independent on TLR4. DC differentiated with URC in combination with IFN-γ might be used on DC-based vaccine for cancer immunotherapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Monoclonal / immunology
  • Antibodies, Monoclonal / pharmacology
  • Antigens, CD / metabolism
  • CD40 Antigens / agonists
  • Cancer Vaccines / immunology
  • Cell Differentiation / drug effects*
  • Cell Differentiation / immunology
  • Cell Proliferation
  • Chemotaxis / drug effects*
  • Chemotaxis / immunology
  • Dendritic Cells / cytology
  • Dendritic Cells / drug effects*
  • Dendritic Cells / immunology*
  • Dendritic Cells / metabolism
  • Enzyme Inhibitors / pharmacology
  • HLA-DR Antigens / metabolism
  • Humans
  • Interferon-alpha / pharmacology
  • Interferon-gamma / immunology
  • Interferon-gamma / pharmacology*
  • Interleukin-10 / metabolism
  • Interleukin-12 / immunology
  • Interleukin-12 / metabolism
  • Interleukin-4 / metabolism
  • Lymphocyte Activation / immunology
  • Lymphocyte Culture Test, Mixed
  • Monocytes / cytology*
  • Monocytes / drug effects
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism
  • Th1 Cells / cytology
  • Th1 Cells / drug effects*
  • Th1 Cells / immunology
  • Th1 Cells / metabolism
  • Toll-Like Receptor 4 / antagonists & inhibitors
  • Toll-Like Receptor 4 / immunology
  • Triterpenes / pharmacology*
  • Tumor Necrosis Factor-alpha / pharmacology

Substances

  • Antibodies, Monoclonal
  • Antigens, CD
  • CD40 Antigens
  • Cancer Vaccines
  • Enzyme Inhibitors
  • HLA-DR Antigens
  • IL10 protein, human
  • IL4 protein, human
  • Interferon-alpha
  • TLR4 protein, human
  • Toll-Like Receptor 4
  • Triterpenes
  • Tumor Necrosis Factor-alpha
  • uncarinic acid-C
  • Interleukin-10
  • Interleukin-12
  • Interleukin-4
  • Interferon-gamma