| Project/Area Number |
20790689
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| Research Category |
Grant-in-Aid for Young Scientists (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
膠原病・アレルギー・感染症内科学
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| Research Institution | Tokyo Medical and Dental University |
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Principal Investigator |
MURAKAMI Yosuki Tokyo Medical and Dental University, 大学院・医歯学総合研究科, メディカルフェロー (30415319)
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| Project Period (FY) |
2008 – 2009
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| Project Status |
Completed (Fiscal Year 2009)
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| Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2009: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Fiscal Year 2008: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
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| Keywords | CDK4 / 6 / macrophage / IRAK1 / p^16<INK4a> / IL-6 / p16^<INK4a> / P16^<INK4a> / LPS / IRAK / AP-1 |
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| Research Abstract |
(This study was conducted to investigate how p16INK4a expression modulates inflammatory cytokine production from macrophages in relation to simple CDK4/6 kinase inhibition. Forced expression of p16INK4a in macrophages suppressed LPS-induced expression of IL-6. The p16INK4a expression accelerated LPS-induced IRAK1 degradation, and suppressed AP-1 pathway. The accelerated IRAK-1 degradation should be mediated by proteasomal degradation because a proteasome inhibitor restored AP-1 activation in p16INK4a-expressing macrophage. Also, IRAK1 overexpression restored IL-6 production in p16INK4a-expressing macrophage. Finally, p16INK4a knock down with siRNA enhanced IL-6 production from senescent macrophage that expressed endogenous p16INK4a. These results showed that p16INK4a suppressed IL-6 production from macrophages in a CDK4/6-independent manner. This was due to proteosome-mediated IRAK1 degradation and following suppression of the AP-1 pathway. Thus, p16INK4a could exert anti-inflammatory effects on synovial macrophages.
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