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

Cell. 2002 Jul 26;110(2):191-202. doi: 10.1016/s0092-8674(02)00827-9.

Abstract

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.

Publication types

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

MeSH terms

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

Substances

  • Adaptor Proteins, Signal Transducing
  • Antigens, Differentiation
  • DNA, Complementary
  • Drosophila Proteins
  • Interleukin-1
  • Interleukin-6
  • Lipopolysaccharides
  • MYD88 protein, human
  • Membrane Glycoproteins
  • Myd88 protein, mouse
  • Myeloid Differentiation Factor 88
  • NF-kappa B
  • Receptors, Cell Surface
  • Receptors, Immunologic
  • TNF Receptor-Associated Factor 6
  • Toll-Like Receptors
  • Tumor Necrosis Factor-alpha
  • Interleukin-12
  • Protein Kinases
  • IRAK3 protein, human
  • Interleukin-1 Receptor-Associated Kinases
  • Irak3 protein, mouse
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases

Associated data

  • GENBANK/AA930623
  • GENBANK/AF461763