A novel regulatory mechanism of cell death in macrophages

• Project/Area Number: 25860322
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Bacteriology (including mycology)
• Research Institution: University of the Ryukyus
• Principal Investigator: TAKAESU Giichi 琉球大学, 医学(系)研究科(研究院), 助教 (60403995)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2014: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2013: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: マクロファージ / 細胞死

Outline of Final Research Achievements

Macrophages often undergo programmed cell death upon microbial infection. Macrophage cell death is positively or negatively regulated by both host and pathogens, which can be beneficial or detrimental to the host depending on the type of pathogens. Currently, it is not fully understood how this programmed cell death is regulated. In this study, I have investigated the roles of TAK1 and its binding protein TAB2 in the control of macrophage cell death. I found that TAK1, but not TAB2, is essential for naive macrophage survival in vitro. Tab2-deficient macrophages underwent cell death when they were stimulated with lipopolysaccharide (LPS), as well as with other TLR ligands including Pam3CSK4, poly I:C or CpG DNA. Moreover, macrophage-specific conditional Tab2 knockout mice were more susceptible to LPS-induced septic shock than wild-type mice. These results may indicate that TAB2 is essential for preventing hyper activation of macrophages in response to LPS in vitro and in vivo.

Research Products

• [Journal Article] Activated macrophage survival is coordinated by TAK1 binding proteins (2014)
  • Author(s): Mihaly SR, Morioka S, Ninomiya-Tsuji J, Takaesu G
  • Journal Title: PLOS ONE Volume: 9 Issue: 4 Pages: e94982-e94982
  • DOI: 10.1371/journal.pone.0094982
  • Peer Reviewed / Open Access
• [Journal Article] TAK1 kinase switches cell fate from apoptosis to necrosis following TNF stimulation (2014)
  • Author(s): Morioka, S., Broglie, P., Omori, E., Ikeda, Y., Takaesu, G. Matsumoto, K., and Ninomiya-Tsuji, J.
  • Journal Title: J, Cell. Biol. Volume: 204 Issue: 4 Pages: 607-623
  • DOI: 10.1083/jcb.201305070
  • Peer Reviewed / Open Access
• [Presentation] TAK1 Kinase Complex Regulates Macrophage Survival (2014)
  • Author(s): 高江洲 義一
  • Organizer: Keystone Symposium, "The Chemistry and Biology of Cell Death"
  • Place of Presentation: 米国ニューメキシコ州サンタフェ市