Final maturation of dendritic cells is associated with impaired responsiveness to IFN-gamma and to bacterial IL-12 inducers: decreased ability of mature dendritic cells to produce IL-12 during the interaction with Th cells.
Activation of immature CD83- dendritic cells (DC) in peripheral tissues induces their maturation and migration to lymph nodes. Activated DC become potent stimulators of Th cells and efficient inducers of Th1- and Th2-type cytokine production. This study analyzes the ability of human monocyte-derived CD1a+ DC at different stages of IL-1 beta and TNF-alpha-induced maturation to produce the major Th1-driving factor IL-12. DC at the early stages of maturation (2 and 4 h) produced elevated amounts of IL-12 p70 during interaction with CD40 ligand-bearing Th cells or, after stimulation with the T cell-replacing factors, soluble CD40 ligand and IFN-gamma. The ability to produce IL-12 was strongly down-regulated at later time points, 12 h after the induction of DC maturation, and in fully mature CD83+ cells, at 48 h. In contrast, the ability of mature DC to produce IL-6 was preserved or even enhanced, indicating their intact responsiveness to CD40 triggering. A reduced IL-12-producing capacity of mature DC resulted mainly from their impaired responsiveness to IFN-gamma, a cofactor in CD40-induced IL-12 p70 production. This correlated with reduced expression of IFN-gamma R (CD119) by mature DC. In addition, while immature DC produced IL-12 and IL-6 after stimulation with LPS or Staphylococcus aureus Cowan I strain, mature DC became unresponsive to these bacterial stimuli. Together with the previously described ability of IL-10 and PGE2 to stably down-regulate the ability to produce IL-12 in maturing, but not in fully mature, DC, the current data indicate a general resistance of mature DC to IL-12-modulating factors.
Kaliński
P
P
Department of Cell Biology and Histology, University of Amsterdam, The Netherlands. p.kalinski@amc.uva.nl
Schuitemaker
J H
JH
Hilkens
C M
CM
Wierenga
E A
EA
Kapsenberg
M L
ML
D000942:Antigens, Bacterial / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D019013:CD40 Antigens / Q000276:immunology / Q000378:metabolism; D002450:Cell Communication / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000166:cytology* / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D018664:Interleukin-12 / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D015850:Interleukin-6 / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000494:pharmacology; D017471:Receptors, Interferon / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D013211:Staphylococcus aureus / Q000276:immunology; D000096743:Interferon gamma Receptor
D000942:Antigens, Bacterial; D019013:CD40 Antigens; D007371:Interferon-gamma; D018664:Interleukin-12; D015850:Interleukin-6; D008070:Lipopolysaccharides; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor