Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UNIPROT:P43026 (lipopolysaccharide)
62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The interleukin-1 receptor-associated kinase (IRAK) was first described as a signal transducer for interleukin-1 (IL-1) and has later been implicated in signal transduction of other members of the Toll/IL-1 receptor family. We now report the identification and characterization of a novel IRAK-like molecule. In contrast to the ubiquitously expressed IRAK and IRAK-2, this new IRAK-like molecule is found mainly in cells of monomyeloic origin and is, therefore, designated IRAK-M. Although IRAK-M and IRAK-2 exhibit only a negligible autophosphorylation activity, they can reconstitute the IL-1 response in a 293 mutant cell line lacking IRAK. In addition, we show for the first time that members of the IRAK family are indispensable elements of lipopolysaccharide signal transduction. The discovery of IRAK-M adds another level of complexity to our understanding of signaling by members of the Toll/IL-1 receptor family.
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PMID:IRAK-M is a novel member of the Pelle/interleukin-1 receptor-associated kinase (IRAK) family. 1038 54

The pro-inflammatory cytokine interleukin-1 (IL-1) signals via the Type-I IL-1 receptor (IL-1RI), inducing an increase in the expression of many genes with roles in immunity and inflammation. The signalling pathways involve two adapter proteins, MyD88 and Tollip, which via two IL-1 receptor-associated kinases (IRAK and IRAK-2) activate transcription factors such as nuclear factor-kappa B and protein kinases such as p38 mitogen-activated protein kinase. A role for the low-molecular-mass G-proteins Rac, Ras and Rap in these processes has also been indicated. IL-1RI is the founder of a diverse superfamily of receptors, which all share a cytosolic domain, termed the Toll/IL-1 receptor (TIR) domain. The superfamily can be divided broadly into three subgroups. The first of these is most similar to IL-1RI and includes the receptor for IL-18 and the Th2 cell regulator T1/ST2. The second subgroup is most similar to the Drosophila melanagaster protein Toll and includes Toll-like receptor 2 (TLR2), which is required for host defence against Gram-positive bacteria and fungi, and TLR4, which is required for lipopolysaccharide responsiveness, and thus is involved in host defence against Gram-negative bacteria. There are also a number of TLRs in plants and insects, all involved in host defence. The third subgroup contains non-receptor proteins which possess a TIR domain and are cytosolic. MyD88 is a member, and it presumably complexes with IL-1RI via a TIR-TIR interaction. The other two members are proteins encoded by the vaccinia virus, A46R and A52R, which block TIR-dependent signalling. This receptor superfamily therefore appears to play a central role in inflammation and host defence against infection, pointing to the TIR domain as a critical molecular player in the innate immune response.
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PMID:The Toll/interleukin-1 receptor domain: a molecular switch for inflammation and host defence. 1104 74

The recognition of microbial pathogens by the innate immune system involves Toll-like receptors (TLRs), which recognize pathogen-associated molecular patterns. Different TLRs recognize different pathogen-associated molecular patterns, with TLR-4 mediating the response to lipopolysaccharide from Gram-negative bacteria. All TLRs have a Toll/IL-1 receptor (TIR) domain, which is responsible for signal transduction. MyD88 is one such protein that contains a TIR domain. It acts as an adapter, being involved in TLR-2, TLR-4 and TLR-9 signalling; however, our understanding of how TLR-4 signals is incomplete. Here we describe a protein, Mal (MyD88-adapter-like), which joins MyD88 as a cytoplasmic TIR-domain-containing protein in the human genome. Mal activates NF-kappaB, Jun amino-terminal kinase and extracellular signal-regulated kinase-1 and -2. Mal can form homodimers and can also form heterodimers with MyD88. Activation of NF-kappaB by Mal requires IRAK-2, but not IRAK, whereas MyD88 requires both IRAKs. Mal associates with IRAK-2 by means of its TIR domain. A dominant negative form of Mal inhibits NF-kappaB, which is activated by TLR-4 or lipopolysaccharide, but it does not inhibit NF-kappaB activation by IL-1RI or IL-18R. Mal associates with TLR-4. Mal is therefore an adapter in TLR-4 signal transduction.
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PMID:Mal (MyD88-adapter-like) is required for Toll-like receptor-4 signal transduction. 1154 29

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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PMID:Severe impairment of interleukin-1 and Toll-like receptor signalling in mice lacking IRAK-4. 1192 71

The interleukin-1 receptor-associated kinases (IRAKs) are important downstream signaling components of Toll-like receptors (TLRs). To date, four mammalian IRAKs have been found, namely IRAK-1, IRAK-2, IRAK-4, and IRAK-M. Herein, we show a detailed analysis of the genomic region encompassing the murine Irak2 gene and the molecular cloning of four isoforms of Irak2 (designated Irak2a, Irak2b, Irak2c, and Irak2d) generated by alternative splicing at the 5'-end of the gene. This alternative splicing has direct effects on the expression of the N-terminal death domain and/or inter-domain. No evidence of similar alternative splicing was found for the human IRAK2 gene. When overexpressed, Irak2a and Irak2b potentiated NF-kappaB activation by lipopolysaccharide. Importantly, Irak2c and Irak2d were inhibitory. The promoter for Irak2c differed from that of the other Irak2 isoforms in that it contained putative NF-kappaB binding sites. Lipopolysaccharide induced the expression of Irak2c, indicating a possible negative feedback effect on the signaling pathway. Alternative splicing of the Irak2 gene in mice will therefore generate agonistic or antagonistic Irak2 isoforms, which is likely to have consequences for the regulation of TLR signaling. These observations identify another distinguishing feature between mice and humans in the TLR system that is likely to be due to differences in the selective pressure imposed by pathogens on each species during evolution.
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PMID:The murine IRAK2 gene encodes four alternatively spliced isoforms, two of which are inhibitory. 1508 13

Vaccinia virus (VV) has many mechanisms to suppress and modulate the host immune response. The VV protein A52R was previously shown to act as an intracellular inhibitor of nuclear factor kappaB (NFkappaB) signaling by Toll-like receptors (TLRs). Co-immunoprecipitation studies revealed that A52R interacted with both tumor necrosis factor receptor-associated factor 6 (TRAF6) and interleukin-1 receptor-associated kinase 2 (IRAK2). The effect of A52R on signals other than NFkappaB was not determined. Here, we show that A52R does not inhibit TLR-induced p38 or c-Jun amino N-terminal kinase (JNK) mitogen activating protein (MAP) kinase activation. Rather, A52R could drive activation of these kinases. Two lines of evidence suggested that the A52R/TRAF6 interaction was critical for these effects. First, A52R-induced p38 MAP kinase activation was inhibited by overexpression of the TRAF domain of TRAF6, which sequestered A52R and inhibited its interaction with endogenous TRAF6. Second, a truncated version of A52R, which interacted with IRAK2 and not TRAF6, was unable to activate p38. Because interleukin 10 (IL-10) production is strongly p38-dependent, we examined the effect of A52R on IL-10 gene induction. A52R was found to be capable of inducing the IL-10 promoter through a TRAF6-dependent mechanism. Furthermore, A52R enhanced lipopolysaccharide/TLR4-induced IL-10 production, while inhibiting the TLR-induced NFkappaB-dependent genes IL-8 and RANTES. These results show that although A52R inhibits NFkappaB activation by multiple TLRs it can simultaneously activate MAP kinases. A52R-mediated enhancement of TLR-induced IL-10 may be important to virulence, given the role of IL-10 in immunoregulation.
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PMID:Vaccinia virus protein A52R activates p38 mitogen-activated protein kinase and potentiates lipopolysaccharide-induced interleukin-10. 1599 38

Alveolar macrophages (AMs) normally respond to lipopolysaccharide (LPS) by activating Toll-like receptor (TLR)-4 signaling, a mechanism critical to lung host defense against gram-negative bacteria such as Pseudomonas aeruginosa. Because granulocyte macrophage colony-stimulating factor (GM-CSF)-deficient (GM(-/-)) mice are hyporesponsive to LPS, we evaluated the role of GM-CSF in TLR-4 signaling in AMs. Pulmonary TNF-alpha levels and neutrophil recruitment 4 h after intratracheal administration of Pseudomonas LPS were reduced in GM(-/-) compared with wild-type (GM(+/+)) mice. Secretion of TNF-alpha by AMs exposed to LPS ex vivo was also reduced in GM(-/-) mice and restored in mice expressing GM-CSF specifically in the lungs (SPC-GM(+/+)/GM(-/-) mice). LPS-dependent NF-kappaB promoter activity, TNF-alpha secretion, and neutrophil chemokine release were reduced in AM cell lines derived from GM(-/-) mice (mAM) compared with GM(+/+) (MH-S). Retroviral expression of PU.1 in mAM cells, which normally lack PU.1, rescued all of these AM defects. To determine whether GM-CSF, via PU.1, regulated expression of TLR-4 pathway components, mRNA and protein levels for key components were evaluated in MH-S cells (GM(+/+), PU.1(Positive)), mAM cells (GM(-/-), PU.1(Negative)), and mAMPU.1+ cells (GM(-/-), PU.1(Positive)). Cluster of differentiation antigen-14, radioprotective 105, IL-1 receptor-associated kinase (IRAK)-M mRNA, and protein were dependent upon GM-CSF and restored by expression of PU.1. In contrast, expression of other TLR-4 pathway components (myeloid differentiation-2, TLR-4, IRAK-1, IRAK-2, Toll/IL-1 receptor domain containing adapter protein/MyD88 adaptor-like, myeloid differentiation primary-response protein 88, IRAK-4, TNF receptor-associated factor-6, NF-kappaB, inhibitor of NF-kappaB kinase) were not GM-CSF or PU.1-dependent. These results show that GM-CSF, via PU.1, enables AM responses to P. aeruginosa LPS by regulating expression of a specific subset of components of the TLR-4 signaling pathway.
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PMID:GM-CSF regulates a PU.1-dependent transcriptional program determining the pulmonary response to LPS. 1691 76

Members of the Pellino family are interleukin-1 receptor-associated kinase (IRAK)-interacting proteins that possess RING-like domains. The presence of these domains led to the suggestion that Pellino proteins are ubiquitin-protein isopeptide ligases (E3). However, no conclusive data currently exist to prove this proposal. This study provides the first direct evidence that Pellino proteins possess E3 activity. Recombinant forms of Pellino1 and Pellino2 and both spliced variants of Pellino3 are shown in an in vitro ubiquitination assay to be E3 ligases that catalyze Lys(63)-linked polyubiquitination, with Pellino3 exhibiting the greatest ligase activity. Whereas the Pellino proteins cause polyubiquitination of IRAK-1, we also show that kinase-active members of the IRAK family (IRAK-1 and IRAK-4) promote reciprocal polyubiquitination of the Pellino proteins and that this is associated with IRAK-induced degradation of the Pellino family. In contrast, IRAK-2 (which lacks a functional kinase domain) and kinase-dead forms of IRAK-1 and IRAK-4 fail to degrade the Pellino proteins. We show that these kinase-inactive IRAK proteins can associate with Pellino proteins, thus excluding the possibility that their inability to regulate Pellino degradation is due to lack of association with the Pellino proteins. The physiological relevance of IRAK-induced degradation of Pellino proteins is confirmed by the demonstration that lipopolysaccharide causes degradation of endogenous forms of Pellino3 in peripheral blood mononuclear cells. In summary, this study not only demonstrates Pellino proteins to be E3 ligases that can catalyze Lys(63)-linked polyubiquitination but also shows bidirectional signaling between the IRAK and Pellino families and highlights a novel function for IRAK kinase activity.
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PMID:Kinase-active interleukin-1 receptor-associated kinases promote polyubiquitination and degradation of the Pellino family: direct evidence for PELLINO proteins being ubiquitin-protein isopeptide ligases. 1767 97

Toll-like receptor 4 (TLR4) recognition of lipopolysaccharide triggers signalosome assembly among TLR4, sorting (e.g. MyD88 adapter-like (Mal)) and signaling (e.g. MyD88) adapters, initiating recruitment and activation of kinases, activation of transcription factors, and production of inflammatory mediators. In this study we examined whether tyrosine phosphorylation of Mal regulates its interactions with TLR4, MyD88, interleukin-1 (IL-1) receptor-associated kinase (IRAK)-2, and tumor necrosis factor receptor-associated factor (TRAF)-6 and is important for signaling. Overexpression of wild-type Mal in human embryonic kidney 293T cells induced its constitutive tyrosine phosphorylation and led to activation of p38, NF-kappaB, and IL-8 gene expression. Mutagenesis of Tyr-86, Tyr-106, and Tyr-159 residues within the Toll-IL-1 receptor domain impaired Mal tyrosine phosphorylation, interactions with Bruton tyrosine kinase, phosphorylation of p38, and NF-kappaB activation. Lipopolysaccharide triggered tyrosine phosphorylation of endogenous Mal and initiated Mal-Bruton-tyrosine kinase interactions in 293/TLR4/MD-2 cells and human monocytes that were suppressed in endotoxin-tolerant cells. Compared with wild-type Mal, Y86A-, Y06A-, and Y159A-Mal variants exhibited higher interactions with TLR4 and MyD88, whereas associations with IRAK-2 and TRAF-6 were not affected. Overexpression of Y86A- and Y106A-Mal in 293/TLR4/MD-2 cells exerted dominant-negative effects on TLR4-inducible p38 phosphorylation and NF-kappaB reporter activation to the extent comparable with P125H-Mal-mediated suppression. In contrast, tyrosine-deficient Mal species did not affect NF-kappaB activation when signaling was initiated at the post-receptor level by overexpression of MyD88, IRAK-2, or TRAF-6. Thus, tyrosine phosphorylation of Mal is required for adapter signaling, regulates Mal interactions with TLR4 and receptor signaling, and is inhibited in endotoxin tolerance.
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PMID:Tyrosine phosphorylation of MyD88 adapter-like (Mal) is critical for signal transduction and blocked in endotoxin tolerance. 1807 Aug 80

To gain insight into microRNAs (miRNAs) involved in the regulation of the human innate immune response, we screened for differentially expressed miRNAs in circulating leukocytes in an in vivo model of acute inflammation triggered by Escherichia coli lipopolysaccharide (LPS) infusion. Leukocyte RNA was isolated from venous blood samples obtained from healthy male volunteers before and 4h after LPS-infusion. After fluorescence labeling, RNA samples were hybridized to microarrays containing capture probes for measuring the abundance of more than 600 human miRNAs. Target genes were predicted for differentially expressed miRNAs and then compared to changes in genome-wide expression levels, which had been established in a previous study. Data analysis revealed that five miRNAs consistently responded to LPS-infusion, four of which were down-regulated (miR-146b, miR-150, miR-342, and let-7g) and one was up-regulated (miR-143). The miR-150 and mir-342 response was confirmed by real-time PCR. By correlating to measured LPS-induced changes of the leukocyte transcriptome, we next searched for predicted target genes, whose stability might be under (co-) control by these miRNAs. We found that the rapid transcriptional activation during acute inflammation of select genes, such as the gene encoding interleukin-1 receptor-associated kinase 2 (IRAK2) might be facilitated by decreased levels of LPS-responsive miRNAs. The increased level of miR-143 might be associated with the pronounced down-regulation of the B-cell CLL/lymphoma 2 (BCL2) gene expression during LPS endotoxemia, and could further be involved in the translational silencing of several other predicted inflammation-related target genes. This is the first in vivo study to demonstrate relative abundance of miRNA levels in peripheral blood leukocytes during acute LPS-induced inflammation. The miRNAs and their potential target genes identified herein contribute to the understanding of the complex transcriptional program of innate immunity initiated by pathogens.
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PMID:In vivo profile of the human leukocyte microRNA response to endotoxemia. 1928 87


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