| Co-Investigator(Kenkyū-buntansha) |
TAKATSUKA Hisakazu University of Fukui, International Social and Health Sciences, Assistant Professor, 医学部, 助手 (40242490)
IWASAKI Hiromichi University of Fukui, General Medicine, Associate Professor, 医学部, 助教授 (10242588)
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| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2005: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 2004: ¥2,400,000 (Direct Cost: ¥2,400,000)
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| Research Abstract |
The immunostimulatory activities of CpG DNA differ with their own sequences. Using polyG-flanked palindromic CpG DNA (unmodified), we examined the mechanisms through which CpG DNA activates plasmacytoid dendritic cells (pDC) in humans.
In pDC, NF-κB family proteins p65 and p50 were constitutively activated. pDC also constitutively expressed IRF-7 and CCL3, and the expression of these genes seemed to be regulated by NF-κB. CpG DNA enhanced the NF-κB p65/p50 activity, which collaborated with p38 MAPK downstream of TLR9 to up-regulate the expressions of IRF-7, CXCL10, and CCL3 in a manner independent of type I IFN signaling. Following the simulation with CpG DNA, IRF-7, both constitutively and newly expressed, moved to the nuclei in a manner independent of NF-κB/p38 MAPK to transcribe the gene for IFN-α. IFN-α, secreted once, returned to pDC and upregulated the expression of IRF-7 independently of NF-κB/p38 MAPK. CpG DNA suppressed IgE production via the activation of pDC.
These findings suggest that (1) there are two pathways in CpG DNA-stimulated human pDC : one dependent on NF-κB and the other independent of NF-κB. The former induces IRF-7, CXCL10, and CCL3, whereas the latter is involved in the activation of IRF-7. (2) IRF-7 induced independently of type I IFN signaling appears to be important for the expression of IFN-α, as the inhibition of NF-κB pathway abrogated the expression of IFN-α. (3) Activation of pDC by CpG DNA would be a promising strategy for inhibiting allergy, as CpG DNA-stimulated pDC suppressed IgE production.
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