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Suzuki, N. et al. Severe impairment of interleukin-1 and Toll-like receptor signalling in mice lacking IRAK-4. Nature 416, 750-756.This study showed the crucial role of IRAK4 in LPS-induced septic shock and TLR and IL1 signalling

Amgen Institute, Ontario Cancer Institute and Department of Medical Biophysics, University of Toronto, 620 University Avenue, Suite 706, Toronto, Ontario M5G 2C1, Canada.
Nature (Impact Factor: 42.35). 05/2002; 416(6882):750-6. DOI: 10.1038/nature736
Source: PubMed

ABSTRACT Toll-like receptors (TLRs), which recognize pathogen-associated molecular patterns, and members of the pro-inflammatory interleukin-1 receptor (IL-1R) family, share homologies in their cytoplasmic domains called Toll/IL-1R/plant R gene homology (TIR) domains. Intracellular signalling mechanisms mediated by TIRs are similar, with MyD88 (refs 5-8) and TRAF6 (refs 9, 10) having critical roles. Signal transduction between MyD88 and TRAF6 is known to involve the serine-threonine kinase IL-1 receptor-associated kinase 1 (IRAK-1) and two homologous proteins, IRAK-2 (ref. 12) and IRAK-M. However, the physiological functions of the IRAK molecules remain unclear, and gene-targeting studies have shown that IRAK-1 is only partially required for IL-1R and TLR signalling. Here we show by gene-targeting that IRAK-4, an IRAK molecule closely related to the Drosophila Pelle protein, is indispensable for the responses of animals and cultured cells to IL-1 and ligands that stimulate various TLRs. IRAK-4-deficient animals are completely resistant to a lethal dose of lipopolysaccharide (LPS). In addition, animals lacking IRAK-4 are severely impaired in their responses to viral and bacterial challenges. Our results indicate that IRAK-4 has an essential role in innate immunity.

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    • "Interestingly, overexpression of IRAK4 mutants containing truncations within the N-terminal kinase domain can suppress IL1-inducible recruitment of wild-type IRAK4 to the IL1R complex, and prevent association with IRAK1, whereas enabling sequestration of MyD88 (Medvedev et al, 2005). In contrast to IRAK1-deficient mice, IRAK4 À / À animals display a severe impairment in inflammatory cytokine expression and NF-kB activation upon challenge with TLR ligands or IL1, and are completely resistant to LPS-mediated septic shock (Suzuki et al, 2002). Additionally, IL1-induced JNK and p38 activation is completely defective in cells lacking IRAK4. "
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    ABSTRACT: Innate immune signalling has an essential role in inflammation, and the dysregulation of signalling components of this pathway is increasingly being recognised as an important mediator in cancer initiation and progression. In some malignancies, dysregulation of inflammatory toll-like receptor (TLR) and interleukin-1 receptor (IL1R) signalling is typified by increased NF-κB activity, and it occurs through somatic mutations, chromosomal deletions, and/or transcriptional deregulation. Interleukin-1 receptor-associated kinase (IRAK) family members are mediators of TLR/IL1R superfamily signalling, and mounting evidence implicates these kinases as viable cancer targets. Although there have been previous efforts aimed at the development of IRAK kinase inhibitors, this is currently an area of renewed interest for cancer drug development.British Journal of Cancer advance online publication, 7 October 2014; doi:10.1038/bjc.2014.513 www.bjcancer.com.
    British Journal of Cancer 10/2014; 112(2). DOI:10.1038/bjc.2014.513 · 4.82 Impact Factor
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    • "The mammalian IRAK-4 differs from DmTube by mainly being involved in immune responses to gram-negative bacterial infections (Swantek et al., 2000; Takeda and Akira, 2005). The bacterial defense function of IRAK-4 has been confirmed in IRAK-4 deficient mice, which showed increased mortality upon a bacterial infection (Suzuki et al., 2002). Recently, in the pacific white shrimp, Litopenaeus vannamei, and the mud crab, Scylla paramamosain, both Gene 541 (2014) 41–50 Abbreviations: DD, death domain; dsRNA, double-stranded RNA; GAPDH, glyceralde- hyde-3-phosphate dehydrogenase; GNBPs, gram-negative binding proteins; LPS, lipopolysaccharides; ORF, open reading frame; PAMPs, pathogen-associated molecular patterns; PG, peptidoglycan; PGRPs, peptidoglycan recognition proteins; PPRs, pattern-recognition receptors; RACE, rapid amplification of cDNA ends; TLRs, Toll-like receptors. "
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    ABSTRACT: As a key component of the Toll signaling pathway, Tube plays central roles in many biological activities, such as survival, development and innate immunity. Tube has been found in shrimps, but has not yet been reported in the crustacean, Eriocheir sinensis. In this study, we cloned the full-length cDNA of the adaptor Tube for the first time from E. sinensis and designated the gene as EsTube. The full-length cDNA of EsTube was 2247-bp with a 1539-bp open reading frame (ORF) encoding a 512-amino acid protein. The protein contained a 116-residue death domain (DD) at its N-terminus and a 272-residue serine/threonine-protein kinase domain (S_TKc) at its C-terminus. Phylogenetic analysis clustered EsTube initially in one group with other invertebrate Tube and Tube-like proteins, and then with the vertebrate IRAK-4 proteins, finally with other invertebrate Pelle proteins. Quantitative real-time polymerase chain reaction (qRT-PCR) analysis results showed that EsTube was highly expressed in the ovary and testis, and moderately expressed in the thoracic ganglia and stomach. EsTube was expressed at all selected stages and was highly expressed in the spermatid stage (October, testis) and the stage III-2 (November, ovary). EsTube was differentially induced after injection of lipopolysaccharides (LPS), peptidoglycan (PG) or zymosan (β-1,3-glucan). Our study indicated that EsTube might possess multiple functions in immunity and development in E. sinensis.
    Gene 03/2014; 541(1). DOI:10.1016/j.gene.2014.03.009 · 2.08 Impact Factor
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    • "The most likely scenario is that once recruited, MyD88 interacts with IL-1 receptor-associated kinase-4 (IRAK-4), via their respective death domains . IRAK-4 then recruits IRAK-1 to the complex, leading to its phosphorylation and activation (Suzuki et al., 2002). IRAK-1 and IRAK-4 then dissociate from the complex and interact with TRAF6 (tumor necrosis factor (TNF) receptor-associated factor-6) (Ninomiya-Tsuji et al., 1999). "
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    ABSTRACT: Myeloid differentiation factor 88 (MyD88) and tumor necrosis factor receptor-associated factor 6 (TRAF6) are two key adaptor molecules in Toll-like receptor signal transduction that triggers downstream cascades involved in innate immunity. Here we reported the isolation and characterization the full-length cDNAs of MyD88 and TRAF6 from sea cucumber Apostichopus japonicus (denoted as AjMyD88 and AjTRAF6, respectively). Both of two factors shared a remarkable high degree of structural conservation with their mammalian and Drosophila orthologs, such as a typical death domain (DD) and a conservative Toll/IL-1R (TIR) domain for the deduced amino acid of AjMyD88, a zinc finger of RING-type, two Zinc fingers of TRAF-type, a coiled-coil region, and a MATH domain for that of AjTRAF6. Constitutive expression patterns were also observed in the two genes with different expression levels. AjMyD88 mRNA transcripts were higher expressed in intestine and respiratory trees, and AjTRAF6 were abundant in coelomocytes and tentacle. During Vibrio splendidus challenge experiment, the expression levels of two genes were increased significantly with larger amplitude and longer duration in AjTRAF6. The peak expression levels were detected at 6h for AjMyD88 with 1.80-fold increase, and at 24h for AjTRAF6 with 2.73-fold increase compared with that in the control group. All these results suggested that AjMyD88 and AjTRAF6 might be involved into immune response towards V. splendidus challenge.
    Developmental and comparative immunology 07/2013; 41(4). DOI:10.1016/j.dci.2013.07.009 · 3.71 Impact Factor
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