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and to Bacterial IL-12 Inducers: Decreased Ability of Mature Dendritic Cells to Produce IL-12 During the Interaction with Th Cells1
Kali
ski2Department of Cell Biology and Histology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
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-1ß and TNF-
-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-
. 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-, a cofactor in CD40-induced IL-12
p70 production. This correlated with reduced expression of IFN-R
(CD119) by mature DC. In addition, while immature DC produced IL-12 and
IL-6 after stimulation with LPS or Staphylococcus aureusCowan 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.
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