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.
Kobayashi
Koichi
K
Section of Immunobiology, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510, USA.
Hernandez
Lorraine D
LD
Galán
Jorge E
JE
Janeway
Charles A
CA
Medzhitov
Ruslan
R
Flavell
Richard A
RA
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000943:Antigens, Differentiation / Q000096:biosynthesis; D001483:Base Sequence; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D003001:Cloning, Molecular; D018076:DNA, Complementary; D029721:Drosophila Proteins; D004926:Escherichia coli / Q000276:immunology; D005260:Female; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D053592:Interleukin-1 Receptor-Associated Kinases; D018664:Interleukin-12 / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D048031:JNK Mitogen-Activated Protein Kinases; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology; D008089:Listeria monocytogenes; D008264:Macrophages / Q000166:cytology / Q000276:immunology / Q000382:microbiology; D008297:Male; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000276:immunology; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000276:immunology; D008969:Molecular Sequence Data; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B / Q000276:immunology; D014176:Protein Biosynthesis; D011494:Protein Kinases / Q000235:genetics / Q000276:immunology*; D011956:Receptors, Cell Surface / Q000276:immunology*; D011971:Receptors, Immunologic / Q000096:biosynthesis; D012480:Salmonella Infections / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D012486:Salmonella typhimurium / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*; D048029:TNF Receptor-Associated Factor 6; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D048051:p38 Mitogen-Activated Protein Kinases
D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; D018076:DNA, Complementary; D029721:Drosophila Proteins; D007375:Interleukin-1; D015850:Interleukin-6; D008070:Lipopolysaccharides; C507779:MYD88 protein, human; D008562:Membrane Glycoproteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D048029:TNF Receptor-Associated Factor 6; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D011494:Protein Kinases; C507771:IRAK3 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases; C507772:Irak3 protein, mouse; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases