Effect of CDK4/6 on innate immunity and osteoclastgenesis.

2009 Fiscal Year Final Research Report

• Project/Area Number: 20790689
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Single-year Grants
• Research Field: 膠原病・アレルギー・感染症内科学
• Research Institution: Tokyo Medical and Dental University
• 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)
• Project Period (FY): 2008 – 2009
• Keywords: CDK4 / 6 / macrophage / IRAK1 / p^16<INK4a> / IL-6

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.