IRAK-4: A novel member of the IRAK family with the properties of an IRAK-kinase
TLDR
IRAK-4 is the closest human homolog to Pelle and depends on its kinase activity to activate NF-κB, suggesting a role of IRAK- 4 as a central element in the early signal transduction of Toll/IL-1 receptors, upstream of IRAk-1.Abstract:
Toll/IL-1 receptor family members are central components of host defense mechanisms in a variety of species. One well conserved element in their signal transduction is Ser/Thr kinases, which couple early signaling events in a receptor complex at the plasma membrane to larger signalosomes in the cytosol. The fruit fly Drosophila melanogaster has one member of this family of kinases, termed Pelle. The complexity of this pathway is vastly increased in vertebrates, and several Pelle homologs have been described and termed IL-1 receptor-associated kinase (IRAK). Here we report the identification of a novel and distinct member of the IRAK family, IRAK-4. IRAK-4 is the closest human homolog to Pelle. Endogenous IRAK-4 interacts with IRAK-1 and TRAF6 in an IL-1-dependent manner, and overexpression of IRAK-4 can activate NF-κB as well as mitogen-activated protein (MAP) kinase pathways. Most strikingly, and in contrast to the other IRAKs, IRAK-4 depends on its kinase activity to activate NF-κB. In addition, IRAK-4 is able to phosphorylate IRAK-1, and overexpression of dominant-negative IRAK-4 is blocking the IL-1-induced activation and modification of IRAK-1, suggesting a role of IRAK-4 as a central element in the early signal transduction of Toll/IL-1 receptors, upstream of IRAK-1.read more
Citations
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Dual Inhibition of Rip2 and IRAK1/4 Regulates IL-1β and IL-6 in Sarcoidosis Alveolar Macrophages and Peripheral Blood Mononuclear Cells.
TL;DR: Data suggest that in sarcoidosis, both pathways, namely IRAK and Rip2, are deregulated, and targeted modulation of Rip2 and IRAK pathways may prove to be a novel treatment for sarCOidosis.
Journal ArticleDOI
Toll-like receptor signaling pathways and the evidence linking toll-like receptor signaling to cardiac ischemia/reperfusion injury.
Yue Wang,Aaron M. Abarbanell,Jeremy L. Herrmann,Brent R. Weil,Jeffrey A. Poynter,Mariuxi C. Manukyan,Paul R. Crisostomo,Daniel R. Meldrum +7 more
TL;DR: The current understanding of the TLR signaling pathways and their roles in the pathophysiology of cardiac ischemia/reperfusion injury are reviewed, as well as several mechanisms for TLR activation and regulation are discussed.
Journal ArticleDOI
Identification of N-(1H-pyrazol-4-yl)carboxamide inhibitors of interleukin-1 receptor associated kinase 4: Bicyclic core modifications
Jongwon Lim,Michael D. Altman,James Baker,Jason D. Brubaker,Hongmin Chen,Yiping Chen,Melanie A. Kleinschek,Chaomin Li,Duan Liu,John Maclean,Erin F. Mulrooney,Jeremy Presland,Larissa Rakhilina,Graham Smith,Ruojing Yang +14 more
TL;DR: A series of permeable N-(1H-pyrazol-4-yl)carboxamides was developed by introducing lipophilic bicyclic cores in place of the polar pyrazolopyrimidine core of 5-amino-N-(1,5-a]pyrimidine-3-car boxamides, leading to the identification of highly permeable IRAK4 inhibitors with excellent potency and kinase selectivity.
Journal ArticleDOI
Alteration of Toll-like receptor 4 activation by 4-hydroxy-2-nonenal mediated by the suppression of receptor homodimerization.
TL;DR: Results demonstrate that 4-HNE blocks TLR4-mediated macrophage activation, gene expression, and phagocytic functions, at least partly by suppressing receptor dimerization, and suggest that 5-hydroxy-2-nonenal influences innate immune responses at sites of infection and inflammation by inhibitingTLR4 activation.
Journal ArticleDOI
Innate immune response to arenaviral infection: a focus on the highly pathogenic New World hemorrhagic arenaviruses.
TL;DR: Current knowledge regarding the interplay between the host innate immune response and NW arenavirus infection in vitro and in vivo is reviewed, with emphasis on viral-encoded proteins and their effect on the type I interferon response.
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