IRAK-4 as the central TIR signaling mediator in innate immunity

Trends Immunol. 2002 Oct;23(10):503-6. doi: 10.1016/s1471-4906(02)02298-6.


Toll-like receptors (TLRs), which recognize pathogen-associated molecular patterns and members of the proinflammatory interleukin-1 receptor (IL-1R) family, share homologies in their cytoplasmic domains. Engagement of members of both of these families initiates a common intracellular signaling cascade, in which MyD88 and tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) are key adaptor proteins. Signaling between MyD88 and TRAF6 is mediated by members of the IL-1R-associated kinase (IRAK) family; however, the exact function of each IRAK protein remains controversial. IRAK-1 is required for the optimal transduction of IL-1R- and TLR-mediated signals, but IRAK-1 can be replaced by other IRAKs. Surprisingly, gene targeting studies show that the newest IRAK protein, IRAK-4, has an essential role in mediating signals initiated by IL-1R and TLR engagement. The kinase activity of IRAK-4 might be necessary to functionally modify IRAK-1 and perhaps other signal transducing substrates. Understanding the role of IRAK-4 in innate immunity will enable us to design novel strategies for therapeutic intervention in human infectious disease.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Drosophila Proteins*
  • Humans
  • Interleukin-1 Receptor-Associated Kinases
  • Lipopolysaccharides / pharmacology
  • Membrane Glycoproteins / immunology*
  • Models, Immunological
  • Phosphotransferases (Alcohol Group Acceptor) / genetics
  • Phosphotransferases (Alcohol Group Acceptor) / immunology*
  • Receptors, Cell Surface / immunology*
  • Signal Transduction
  • Toll-Like Receptors


  • Drosophila Proteins
  • Lipopolysaccharides
  • Membrane Glycoproteins
  • Receptors, Cell Surface
  • Toll-Like Receptors
  • Phosphotransferases (Alcohol Group Acceptor)
  • Interleukin-1 Receptor-Associated Kinases