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Departments of
*
Cell Processing,
Clinical Immunology and AIDS Research Center, and
Hematology/Oncology, Institute of Medical Science, University of Tokyo, Tokyo, Japan; and
§
Japanese Red Cross Central Blood Center, Tokyo, Japan
We analyzed the expression of IL-12Rß1 and IL-12Rß2 and the
role of IL-12 in the activation of monocyte-derived dendritic cells
(DCs) via IL-12Rß1-mediated signaling events. Flow cytometric
analysis revealed that IL-12Rß1 was expressed in T cells, Con A
blasts, and monocyte-derived DCs, but not in monocytes, while its
transcript was detected in all of these cell types. Transcriptional
expression of IL-12Rß2 was observed in T cells, Con A blasts, and
monocyte-derived DCs, but not monocytes. The ligation of DCs as well as
Con A blasts by IL-12 induced the production of GM-CSF, IL-1ß, IL-6,
TNF-
, and IFN-
at the transcription levels. Furthermore,
stimulation of DCs with IL-12 induced IL-12p40 transcript, but not
IL-12p35 transcript, whereas this stimulation caused the expressions of
both transcripts in Con A blasts. Stimulation of DCs with IL-12 caused
a tyrosine phosphorylation of several intracellular proteins, and the
pattern of these events were distinct from those of IL-12-stimulated
Con A blasts. IL-12 also induced tyrosine phosphorylation of IL-12Rß1
as well as recruitment of several tyrosine-phosphorylated proteins to
IL-12Rß1 in DCs and Con A blasts. Receptor engagement of DCs as well
as Con A blasts by IL-12 resulted in activation of Janus kinase 2 and
Tyk2 kinases and Stat3 and Stat4 transcription factors and the
association of these proteins to IL-12Rß1. Stimulation with IL-12
caused a tyrosine phosphorylation and enzymatic activity of a family of
mitogen-activated protein kinases, p38mapk. These results
suggest that IL-12 acts directly on DCs to induce their functional
activation via IL-12Rß1-mediated signaling events.
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