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 RIS Download
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