TNF-alpha drives human CD14+ monocytes to differentiate into CD70+ dendritic cells evoking Th1 and Th17 responses

J Immunol. 2007 Aug 1;179(3):1449-57. doi: 10.4049/jimmunol.179.3.1449.


Many mechanisms involving TNF-alpha, Th1 responses, and Th17 responses are implicated in chronic inflammatory autoimmune disease. Recently, the clinical impact of anti-TNF therapy on disease progression has resulted in re-evaluation of the central role of this cytokine and engendered novel concept of TNF-dependent immunity. However, the overall relationship of TNF-alpha to pathogenesis is unclear. Here, we demonstrate a TNF-dependent differentiation pathway of dendritic cells (DC) evoking Th1 and Th17 responses. CD14(+) monocytes cultured in the presence of TNF-alpha and GM-CSF converted to CD14(+) CD1a(low) adherent cells with little capacity to stimulate T cells. On stimulation by LPS, however, they produced high levels of TNF-alpha, matrix metalloproteinase (MMP)-9, and IL-23 and differentiated either into mature DC or activated macrophages (M phi). The mature DC (CD83(+) CD70(+) HLA-DR (high) CD14(low)) expressed high levels of mRNA for IL-6, IL-15, and IL-23, induced naive CD4 T cells to produce IFN-gamma and TNF-alpha, and stimulated resting CD4 T cells to secret IL-17. Intriguingly, TNF-alpha added to the monocyte culture medium determined the magnitude of LPS-induced maturation and the functions of the derived DC. In contrast, the M phi (CD14(high)CD70(+)CD83(-)HLA-DR(-)) produced large amounts of MMP-9 and TNF-alpha without exogenous TNF stimulation. These results suggest that the TNF priming of monocytes controls Th1 and Th17 responses induced by mature DC, but not inflammation induced by activated M phi. Therefore, additional stimulation of monocytes with TNF-alpha may facilitate TNF-dependent adaptive immunity together with GM-CSF-stimulated M phi-mediated innate immunity.

Publication types

  • Comparative Study

MeSH terms

  • CD27 Ligand / biosynthesis*
  • Cell Differentiation / immunology*
  • Cells, Cultured
  • Dendritic Cells / immunology*
  • Dendritic Cells / metabolism
  • Dendritic Cells / pathology
  • Granulocyte-Macrophage Colony-Stimulating Factor / physiology
  • Humans
  • Inflammation Mediators / physiology
  • Interleukin-17 / biosynthesis*
  • Interleukin-23 / physiology
  • Lipopolysaccharide Receptors / biosynthesis*
  • Macrophages / immunology
  • Macrophages / metabolism
  • Macrophages / pathology
  • Models, Immunological
  • Monocytes / immunology*
  • Monocytes / metabolism
  • Monocytes / pathology
  • Myeloid Progenitor Cells / immunology
  • Myeloid Progenitor Cells / metabolism
  • Myeloid Progenitor Cells / pathology
  • Th1 Cells / immunology*
  • Th1 Cells / metabolism
  • Th1 Cells / pathology
  • Tumor Necrosis Factor-alpha / physiology*


  • CD27 Ligand
  • Inflammation Mediators
  • Interleukin-17
  • Interleukin-23
  • Lipopolysaccharide Receptors
  • Tumor Necrosis Factor-alpha
  • Granulocyte-Macrophage Colony-Stimulating Factor