TGF-beta and vitamin D3 utilize distinct pathways to suppress IL-12 production and modulate rapid differentiation of human monocytes into CD83+ dendritic cells

J Immunol. 2005 Feb 15;174(4):2061-70. doi: 10.4049/jimmunol.174.4.2061.

Abstract

We previously demonstrated that agents known to signal infection or inflammation can rapidly and directly drive differentiation of human CD14+ monocytes into CD83+ dendritic cells (DCs) when introduced to cells under serum-free conditions. In this study, we evaluated the effects of TGF-beta and vitamin D3 (VitD3) on the proportion and function of monocytes that adopt DC characteristics. TGF-beta significantly decreased the proportion of cells that rapidly adopted stable DC characteristics in response to LPS, but had little or no effect on calcium ionophore-induced differentiation. In contrast, VitD3 showed no such pathway specificity and dramatically suppressed differentiation of monocytes into DCs in response to these agents. Both TGF-beta and VitD3 altered cytokine and chemokine production in LPS-treated monocytes, inhibited IL-12 and IL-10 secretion, and decreased the functional capacity of DCs. Despite the similar effects of TGF-beta and VitD3, there are significant differences in the signaling pathways used by these agents, as evidenced by their distinct effects on LPS- and calcium ionophore-induced DC differentiation, on LPS-induced secretion of IL-10, and on two members of the NF-kappaB family of transcription factors, RelB and cRel. These studies identify TGF-beta and VitD3 as potent regulatory factors that use distinct pathways to suppress both the differentiation of DCs as well as their capacity to secrete the Th1-polarizing cytokine IL-12. Because these agents are present in serum and negatively affect DC differentiation at physiological concentrations, our findings are likely to have significance regarding the in vivo role of TGF-beta and VitD3 in determining the type of immune responses.

Publication types

  • Comparative Study

MeSH terms

  • Active Transport, Cell Nucleus / immunology
  • Antigen-Presenting Cells / immunology
  • Antigens, CD
  • CD83 Antigen
  • Cell Differentiation / immunology
  • Cells, Cultured
  • Cholecalciferol / physiology*
  • Culture Media, Serum-Free
  • DNA-Binding Proteins / metabolism
  • Dendritic Cells / immunology*
  • Dendritic Cells / metabolism
  • Down-Regulation / immunology
  • Humans
  • Immunoglobulins / biosynthesis*
  • Immunologic Factors / physiology*
  • Immunophenotyping
  • Interleukin-12 / antagonists & inhibitors*
  • Interleukin-12 / biosynthesis*
  • Lipopolysaccharides / antagonists & inhibitors
  • Lipopolysaccharides / pharmacology
  • Lymphocyte Culture Test, Mixed
  • Membrane Glycoproteins / biosynthesis*
  • Monocytes / cytology
  • Monocytes / immunology
  • Monocytes / metabolism
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / metabolism
  • Receptors, Cell Surface / biosynthesis
  • Signal Transduction / immunology*
  • Smad Proteins
  • Toll-Like Receptors
  • Trans-Activators / metabolism
  • Transforming Growth Factor beta / physiology*
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Antigens, CD
  • Culture Media, Serum-Free
  • DNA-Binding Proteins
  • Immunoglobulins
  • Immunologic Factors
  • Lipopolysaccharides
  • Membrane Glycoproteins
  • NF-kappa B
  • Receptors, Cell Surface
  • Smad Proteins
  • Toll-Like Receptors
  • Trans-Activators
  • Transforming Growth Factor beta
  • Interleukin-12
  • Cholecalciferol
  • p38 Mitogen-Activated Protein Kinases