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IRAK-M is a negative regulator of Toll-like receptor signaling.

Toll-like receptors (TLRs) detect microorganisms and protect multicellular organisms from infection. TLRs transduce their signals through MyD88 and the serine/threonine kinase IRAK. The IRAK family consists of two active kinases, IRAK and IRAK-4, and two inactive kinases, IRAK-2 and IRAK-M. IRAK-M expression is restricted to monocytes/macrophages, whereas other IRAKs are ubiquitous. We show here that IRAK-M is induced upon TLR stimulation and negatively regulates TLR signaling. IRAK-M prevented dissociation of IRAK and IRAK-4 from MyD88 and formation of IRAK-TRAF6 complexes. IRAK-M(-/-) cells exhibited increased cytokine production upon TLR/IL-1 stimulation and bacterial challenge, and IRAK-M(-/-) mice showed increased inflammatory responses to bacterial infection. Endotoxin tolerance, a protection mechanism against endotoxin shock, was significantly reduced in IRAK-M(-/-) cells. Thus, IRAK-M regulates TLR signaling and innate immune homeostasis.

Pubmed ID: 12150927


  • Kobayashi K
  • Hernandez LD
  • Gal├ín JE
  • Janeway CA
  • Medzhitov R
  • Flavell RA



Publication Data

July 26, 2002

Associated Grants


Mesh Terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Antigens, Differentiation
  • Base Sequence
  • Cell Line, Transformed
  • Cells, Cultured
  • Cloning, Molecular
  • DNA, Complementary
  • Drosophila Proteins
  • Escherichia coli
  • Female
  • Humans
  • Interleukin-1
  • Interleukin-1 Receptor-Associated Kinases
  • Interleukin-12
  • Interleukin-6
  • JNK Mitogen-Activated Protein Kinases
  • Lipopolysaccharides
  • Listeria monocytogenes
  • Macrophages
  • Male
  • Membrane Glycoproteins
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases
  • Molecular Sequence Data
  • Myeloid Differentiation Factor 88
  • NF-kappa B
  • Protein Biosynthesis
  • Protein Kinases
  • Receptors, Cell Surface
  • Receptors, Immunologic
  • Salmonella Infections
  • Salmonella typhimurium
  • Signal Transduction
  • TNF Receptor-Associated Factor 6
  • Toll-Like Receptors
  • Tumor Necrosis Factor-alpha
  • p38 Mitogen-Activated Protein Kinases