2005 Fiscal Year Final Research Report Summary
Inhibitory mechanism and the target of Toll like receptor signaling inhibitors
| Project/Area Number |
16590367
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Bacteriology (including Mycology)
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| Research Institution | Gifu Pharmaceutical University |
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Principal Investigator |
SUGIYAMA Tsuyoshi Gifu Pharmaceutical Univ, Dept. Public Health Pharmacy, Assistant Professor, 薬学部, 助教授 (70268001)
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| Project Period (FY) |
2004 – 2005
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| Keywords | Toll-like receptors / Lipopolysaccharides / poly I : C / Bacterial CpG DNA / Nitric Oxide / Cytokines / Signaltransduction |
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| Research Abstract |
Toll like receptor (TLR) have been identified as homologues of the Drosophila protein Toll, and is recognized as key players in innate immune system recognizing microbial components. We previously found that 2-aminopurine (2-AP) inhibits TLR stimulated-nitric oxide production followed by suppressing IFN-β production. In this study, we analyzed the detail mechanism of inhibitory effect of 2-AP and screened some 2-AP analogues for TLR signaling inhibitor
In mouse macrophage cell line RAW264, LPS and poly I:C stimulate IL-6 and TNF-α production. 2-AP inhibited IL-6 production effectively, whereas TNF-α production was partially inhibited. LPS- or poly I:C-stimulated IFN-β promoter and ISRE activity were completely inhibited, but NF-κB activation was inhibited partially. Furthermore, IFN-β promoter activity in TBK1-overexpressed HEK293 cells was inhibited by adding 2-AP. Taken together, these results suggest that the target molecule of 2-AP in inhibition of LPS or poly I:C signaling is located in the downstream of TBK1.
Several compounds analogous to 2-AP were tested on the inhibitory effect of TLR-stimulated nitric oxide production. Some 9-benzyladenine derivatives were found to inhibit LPS-stimulated nitric oxide production in lower concentration than 2-AP, suggested to be lead compounds for inhibitors of TLR signaling.
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Research Products
(6 results)
