IRAK-M is a negative regulator of Toll-like receptor signaling.
Journal:
Cell 2002 JulAuthors:
Kobayashi K, Hernandez LD, Galán JE, Janeway CA, Medzhitov R, Flavell RA
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
...[more]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.[less]
Mesh Headings:
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