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

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

The phenomenon of endotoxin tolerance has been widely investigated, but to date, the molecular mechanisms of endotoxin tolerance remain to be resolved clearly. The discovery of the Toll-like receptor (TLR) family as the major receptors for lipopolysaccharide (LPS) and other bacterial products has prompted a resurgence of interest in endotoxin tolerance mechanisms. Changes of cell surface molecules, signaling proteins, pro-inflammatory and anti-inflammatory cytokines and other mediators have been examined. During tolerance expression of LPS-binding protein (LBP), CD14, myeloid differentiation protein-2 (MD-2) and TLR2 are unchanged or up-regulated, whereas TLR4 is transiently suppressed or unchanged. Proximal post-receptor signaling proteins that are altered in tolerance include augmented degradation of interleukin-1 receptor-associated kinase (IRAK), and decreased TLR4-myeloid differentiation factor 88 (MyD88) and IRAK-MyD88 association. Tolerance has also been shown to be associated with decreased Gi protein content and activity, decreased protein kinase C (PKC) activity, reduction in mitogen-activated protein kinase (MAP kinase) activity, and reduced activator protein-1 (AP-1) and nuclear factor kappa B (NF-kappaB) induced gene transactivation. However, not all signaling proteins and pathways are suppressed in tolerance and induction of specific anti-inflammatory proteins and signaling pathways may serve important counter inflammatory functions. The latter include induction of IRAK-M and suppressor of cytokine-signaling-1 (SOCS-1), phosphoinositide-3-kinase (PI3K) signaling, and increased or maintained expression of inhibitor-kappaB (IkappaB) isoforms. Also at the nuclear level, increase in the NF-kappaB subunit p50 homodimer expression and increased activation of peroxisome-proliferator-activated receptors-gamma (PPARgamma) have been linked to tolerance phenotype. Although there are species and cellular variations in manifestation of the LPS tolerant phenotype, it is clear that the tolerance phenomena have evolved as a complex orchestrated counter regulatory response to inflammation.
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PMID:Molecular mechanisms of endotoxin tolerance. 1511 98

Mannose-capped lipoarabinomannans (Man-LAMs) are members of the repertoire of Mycobacterium tuberculosis modulins that the bacillus uses to subvert the host innate immune response. Interleukin-12 (IL-12) production is critical for mounting an effective immune response by the host against M. tuberculosis. We demonstrate that Man-LAM inhibits IL-12 p40 production mediated by subsequent challenge with lipopolysaccharide (LPS). Man-LAM inhibits LPS-induced IL-12 p40 expression in an IL-10-independent manner. It attenuates LPS-induced NF-kappaB-driven luciferase gene expression, suggesting that its effects are likely directly related to inhibition of NF-kappaB. This is probably because of dampening of the Toll-like receptor signaling. Man-LAM inhibits IL-1 receptor-associated kinase (IRAK)-TRAF6 interaction as well as IkappaB-alpha phosphorylation. It directly attenuates nuclear translocation and DNA binding of c-Rel and p50. Man-LAM exerts these effects by inducing the expression of Irak-M, a negative regulator of TLR signaling. Knockdown of Irak-M expression by RNA interference reinstates LPS-induced IL-12 production in Man-LAM-pretreated cells. The fact that Irak-M expression could be elicited by yeast mannan suggested that ligation of the mannose receptor by the mannooligosaccharide caps of LAM was the probable trigger for IRAK-M induction.
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PMID:Mycobacterium tuberculosis lipoarabinomannan-mediated IRAK-M induction negatively regulates Toll-like receptor-dependent interleukin-12 p40 production in macrophages. 1626 13

Rheumatoid arthritis (RA) is characterized by infiltrations of inflammatory cells accompanied by neovascularization in the joint. We hypothesized that cell activation via the toll-like receptor (TLR) may be involved in the induction of angiogenic molecules, which are relevant to the pathogenesis of RA. RA fibroblast like synoviocytes (FLS) were stimulated with TLR-2 ligand bacterial peptidoglycan (PGN), TLR-4 ligand lipopolysaccharide (LPS) and various cytokines. Vascular endothelial growth factor (VEGF) and IL-8 were measured by ELISA in culture supernatants; mRNA levels were assessed by RT-PCR and real time PCR. The levels of TLR-2, VEGF and IL-8 were analyzed by dual immunohistochemistry in RA synovium and compared with osteoarthritis (OA). Regulation of MyD88, IRAK4, IRAK1, IRAK-M and TRAF-6 mRNA expression levels by PGN were analyzed by RT-PCR. Phosphorylation of I kappa B alpha was evaluated by western blotting. Levels of VEGF and IL-8 were upregulated in culture supernatants of RA FLS stimulated with PGN, similar to the levels of IL-1beta and IL-17 stimulation. Neutralization of TLR-2 with a blocking monoclonal antibody significantly reduced both VEGF and IL-8 levels (P<0.05), which reflected the functional relevance of TLR-2 activation to the induction of VEGF and IL-8 production. Downstream intracellular signaling following TLR-2 stimulation involved MyD88-IRAK-4-TRAF-6 pathways, resulting in NF-kappaB activation. Thus, TLR-2 activation in RA FLS by microbial constituents could be involved in the induction of VEGF and IL-8 and thereby promote inflammation either directly or via angiogenesis. This possibly contributes to the perpetuation of synovitis in patients with RA.
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PMID:Toll-like receptor 2 ligand mediates the upregulation of angiogenic factor, vascular endothelial growth factor and interleukin-8/CXCL8 in human rheumatoid synovial fibroblasts. 1718 9

Impairment of the ability to mount an inflammatory response is associated with death from adult critical illness. This phenomenon, characterized by reduced monocyte production of proinflammatory mediators such as tumor necrosis factor alpha (TNF-alpha), is poorly understood in children. We hypothesized that differential expression of inflammation-related genes would be seen in monocytes from children with adverse outcomes from multiple organ dysfunction syndrome (MODS). Ex vivo lipopolysaccharide (LPS)-induced TNF-alpha production and plasma cytokines were prospectively measured biweekly in children with dysfunction of two or more organs. Concomitantly, monocyte expression of 28 pro- and anti-inflammatory genes [cytokines, Toll-like receptor (TLR)/nuclear factor kappaB (NF-kappaB) signaling pathway members, inflammasome elements] was measured. Thirty children (22 survivors, eight nonsurvivors) were evaluated. High mRNA levels for interleukin (IL)-10, IL-1 receptor-associated kinase (IRAK-M), and the putative inflammasome inhibitor pyrin were associated with death (p < or = 0.02). Plasma IL-10 levels were higher and ex vivo TNF-alpha production was lower in nonsurvivors (p < 0.05). Among survivors, high mRNA levels for IL-10, IRAK-M, pyrin, IRAK1, or TLR4 were associated with longer durations of pediatric intensive care unit (PICU) stay and mechanical ventilation (p < or = 0.02). These data suggest that adverse outcomes from pediatric MODS are associated with an anti-inflammatory monocyte mRNA phenotype. Future studies are warranted to explore mechanisms of immunodepression in pediatric critical illness.
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PMID:Monocyte mRNA phenotype and adverse outcomes from pediatric multiple organ dysfunction syndrome. 1780 2

The intrahepatic biliary tree is a conduit of bile which contains pathogen-associated molecular patterns (PAMPs) such as lipopolysaccharide (LPS) originated from intestinal flora. Human biliary epithelial cells (BEC) express toll-like receptors (TLR) and intracellular adaptor molecules and secrete antibiotic peptides and (pro)inflammatory cytokines via the activation of nuclear transcription factors. However, although human bile contains several PAMPs in normal as well as diseased livers, PAMPs physiologically do not elicit an inflammatory response in the biliary tree, suggesting that tolerance against commensal PAMPs including LPS (endotoxin tolerance) is important in maintaining the homeostasis of biliary innate immunity. Negative regulators of intracellular TLR signalings, peroxisome proliferator activating receptor-gamma (PPAR-gamma) and IRAK-M, are associated with the endotoxin tolerance in BEC. In vivo, PPAR-gamma and IRAK-M are ubiquitously expressed in intrahepatic biliary epithelium, while the expression of PPAR-gamma is reduced in damaged bile ducts of primary biliary cirrhosis (PBC). In addition to antibiotic peptides, several cytokines andchemokines are also secreted from BEC as an innate immune response and these humoral components participate in attracting immunocytes and modulating peribiliary cytokine milieu. BEC have receptors for several cytokines and the expression of TLR in BEC is affected by cytokines, suggesting that biliary innate immunity is regulated by an acquired immunity. A T-helper (Th)1-type cytokine, interferon-gamma, downregulates PPAR-gamma and upregulates TLR, and consequently increases the susceptibility of biliary innate immunity. Because periductal cytokine milieu in PBC is Th1-dominant, the increased susceptibility to PAMPs may be associated with the development of cholangiopathy in PBC. Biliary innate immunity is speculated to be associated with the pathogenesis of biliary diseases as well as the defense against biliary microbial infection.
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PMID:Biliary innate immunity and cholangiopathy. 1793 Nov 98

Although innate signals driven by Toll-like receptors (TLRs) play a crucial role in T-dependent immune responses and serological memory, the precise cellular and time-dependent requirements for such signals remain poorly defined. To directly address the role for B cell-intrinsic TLR signals in these events, we compared the TLR response profile of germinal center (GC) versus naive mature B cell subsets. TLR responsiveness was markedly up-regulated during the GC reaction, and this change correlated with altered expression of the key adaptors MyD88, Mal, and IRAK-M. To assess the role for B cell-intrinsic signals in vivo, we transferred MyD88 wild-type or knockout B cells into B cell-deficient microMT mice and immunized recipient animals with 4-hydroxy-3-nitrophenylacetyl (NP) chicken gamma globulin. All recipients exhibited similar increases in NP-specific antibody titers during primary, secondary, and long-term memory responses. The addition of lipopolysaccharide to the immunogen enhanced B cell-intrinsic, MyD88-dependent NP-specific immunoglobulin (Ig)M production, whereas NP-specific IgG increased independently of TLR signaling in B cells. Our data demonstrate that B cell-intrinsic TLR responses are up-regulated during the GC reaction, and that this change significantly promotes antigen-specific IgM production in association with TLR ligands. However, B cell-intrinsic TLR signals are not required for antibody production or maintenance.
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PMID:B cell intrinsic TLR signals amplify but are not required for humoral immunity. 1803 50

Among the multiple mechanisms that control the intensity and duration of macrophage activation, the development of a state of refractoriness to a second stimulation in cells treated with lipopolysaccharide (LPS) has long been recognized. Release of inhibitory cytokines and alterations in intracellular signaling pathways may be involved in the development of LPS tolerance. Although a number of molecules have been implicated, a detailed picture of the molecular changes in LPS tolerance is still missing. We have used a genome-wide gene expression analysis approach to (i) define which fraction of LPS target genes are subject to tolerance induction and (ii) identify genes that are expressed at high levels in tolerant macrophages. Our data show that in LPS-tolerant macrophages the vast majority of LPS-induced gene expression is abrogated. The extent of tolerance induction varies for individual genes, and a small subset of genes appears to be exempted. Compared to other negative control mechanisms of macrophages, e.g., IL-10-induced deactivation, LPS tolerance inhibits a much wider range of transcriptional targets. Some previously described negative regulators of TLR signaling (e.g. IRAK-M) were confirmed as expressed at higher levels in LPS-tolerant macrophages. In addition, we discuss other potential players in LPS tolerance identified in this group of genes.
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PMID:A genome-wide analysis of LPS tolerance in macrophages. 1808 74


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