Interferon-gamma dose-dependently inhibits prostaglandin E2-mediated dendritic-cell-migration towards secondary lymphoid organ chemokines.
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.
Alder
John
J
Institution of Laboratory Medicine, Department of Clinical Immunology, The Sahlgrenska University Hospital, Göteborg, Sweden.
Hahn-Zoric
Mirjana
M
Andersson
Bengt A
BA
Karlsson-Parra
Alex
A
D015703:Antigens, CD / Q000276:immunology; D000998:Antiviral Agents / Q000494:pharmacology*; D002465:Cell Movement / Q000187:drug effects; D018925:Chemokines / Q000502:physiology*; D003470:Culture Media; D003713:Dendritic Cells / Q000187:drug effects*; D015232:Dinoprostone / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000235:genetics; D006801:Humans; D007202:Indicators and Reagents; D007371:Interferon-gamma / Q000494:pharmacology*; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008198:Lymph Nodes / Q000166:cytology; D008221:Lymphoid Tissue / Q000166:cytology* / Q000378:metabolism*; D009000:Monocytes / Q000276:immunology; D010641:Phenotype; D011448:Prostaglandin Antagonists; D054400:Receptors, CCR7; D019707:Receptors, Chemokine / Q000235:genetics; D011994:Recombinant Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D015703:Antigens, CD; D000998:Antiviral Agents; C515370:CCR7 protein, human; D018925:Chemokines; D003470:Culture Media; D007202:Indicators and Reagents; D053583:Interleukin-1beta; D015850:Interleukin-6; D011448:Prostaglandin Antagonists; D054400:Receptors, CCR7; D019707:Receptors, Chemokine; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D015232:Dinoprostone