Interferon-gamma dose-dependently inhibits prostaglandin E2-mediated dendritic-cell-migration towards secondary lymphoid organ chemokines

Vaccine. 2006 Nov 30;24(49-50):7087-94. doi: 10.1016/j.vaccine.2006.07.002. Epub 2006 Jul 18.

Abstract

Monocyte-derived human dendritic cells (MoDCs) are increasingly applied as cellular vaccines for cancer patients. Important features for their efficacy include high migratory responsiveness to lymph node-chemokines and most likely their ability to produce bioactive IL-12 p70 upon subsequent contact with CD40 ligand-expressing T-cells. The current standard DC-maturation cocktail for clinical trials is inflammatory cytokines (TNF-alpha, IL-1beta and IL-6) combined with prostaglandin E(2) (PGE(2)), inducing phenotypically mature MoDCs with high migratory responsiveness to CCR7 ligands. This cocktail does not, however, induce or prime for production of IL-12 p70. Addition of IFN-gamma to PGE(2)-containing maturation cocktails has been shown to prime for substantial production of IL-12 p70 by subsequent CD40 ligation, but the impact of IFN-gamma on phenotypic maturation and migratory responsiveness induced by PGE(2)-containing inflammatory stimuli still remains elusive. Here, we demonstrate that addition of IFN-gamma to the standard maturation cocktail decreased CCR7 mRNA and down-regulated CCR7 expression on MoDCs in a dose-dependent manner. Moreover, addition of IFN-gamma was found to suppress MoDC-migration towards the CCR7-ligands CCL19 and CCL21. These novel findings indicate that addition of IFN-gamma to DC-maturation stimuli may have no beneficial impact on MoDC-vaccine efficiency and further implicate IFN-gamma as a negative feedback factor in DC migration towards draining lymph nodes when full-blown Th1-type responses are established. Such mechanism may restrict an uncontrolled and potentially harmful amplification of the adaptive Th1 response.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, CD / immunology
  • Antiviral Agents / pharmacology*
  • Cell Movement / drug effects
  • Chemokines / physiology*
  • Culture Media
  • Dendritic Cells / drug effects*
  • Dinoprostone / physiology*
  • Dose-Response Relationship, Drug
  • Glyceraldehyde-3-Phosphate Dehydrogenases / genetics
  • Humans
  • Indicators and Reagents
  • Interferon-gamma / pharmacology*
  • Interleukin-1beta / metabolism
  • Interleukin-6 / metabolism
  • Lymph Nodes / cytology
  • Lymphoid Tissue / cytology*
  • Lymphoid Tissue / metabolism*
  • Monocytes / immunology
  • Phenotype
  • Prostaglandin Antagonists*
  • Receptors, CCR7
  • Receptors, Chemokine / genetics
  • Recombinant Proteins
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Antigens, CD
  • Antiviral Agents
  • CCR7 protein, human
  • Chemokines
  • Culture Media
  • Indicators and Reagents
  • Interleukin-1beta
  • Interleukin-6
  • Prostaglandin Antagonists
  • Receptors, CCR7
  • Receptors, Chemokine
  • Recombinant Proteins
  • Tumor Necrosis Factor-alpha
  • Interferon-gamma
  • Glyceraldehyde-3-Phosphate Dehydrogenases
  • Dinoprostone