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)

TANK-binding kinase-1 (TBK1) and the inducible IkappaB kinase (IKK-i) have been shown recently to activate interferon (IFN) regulatory factor-3 (IRF3), the primary transcription factor regulating induction of type I IFNs. Here, we have compared the role and specificity of TBK1 in the type I IFN response to lipopolysaccharide (LPS), polyI:C, and viral challenge by examining IRF3 nuclear translocation, signal transducer and activator of transcription 1 phosphorylation, and induction of IFN-regulated genes. The LPS and polyI:C-induced IFN responses were abolished and delayed, respectively, in macrophages from mice with a targeted disruption of the TBK1 gene. When challenged with Sendai virus, the IFN response was normal in TBK1(-/-) macrophages, but defective in TBK1(-/-) embryonic fibroblasts. Although both TBK1 and IKK-i are expressed in macrophages, only TBK1 but not IKK-i was detected in embryonic fibroblasts by Northern blotting analysis. Furthermore, the IFN response in TBK1(-/-) embryonic fibroblasts can be restored by reconstitution with wild-type IKK-i but not a mutant IKK-i lacking kinase activity. Thus, our studies suggest that TBK1 plays an important role in the Toll-like receptor-mediated IFN response and is redundant with IKK-i in the response of certain cell types to viral infection.
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PMID:Differential requirement for TANK-binding kinase-1 in type I interferon responses to toll-like receptor activation and viral infection. 1521 Jul 43

Numerous bacterial products such as lipopolysaccharide potently induce type I interferons (IFNs); however, the contribution of this innate response to host defense against bacterial infection remains unclear. Although mice deficient in either IFN regulatory factor (IRF)3 or the type I IFN receptor (IFNAR)1 are highly susceptible to viral infection, we show that these mice exhibit a profound resistance to infection caused by the Gram-positive intracellular bacterium Listeria monocytogenes compared with wild-type controls. Furthermore, this enhanced bacterial clearance is accompanied by a block in L. monocytogenes-induced splenic apoptosis in IRF3- and IFNAR1-deficient mice. Thus, our results highlight the disparate roles of type I IFNs during bacterial versus viral infections and stress the importance of proper IFN modulation in host defense.
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PMID:Type I interferon production enhances susceptibility to Listeria monocytogenes infection. 1530 1

An understanding of lipopolysaccharide (LPS) signal transduction is a key goal in the effort to provide a molecular basis for the lethal effect of LPS during septic shock and point the way to novel therapies. Rapid progress in this field during the last 6 years has resulted in the discovery of not only the receptor for LPS - Toll-like receptor 4 (TLR4) - but also in a better appreciation of the complexity of the signalling pathways activated by LPS. Soon after the discovery of TLR4, the formation of a receptor complex in response to LPS, consisting of dimerized TLR4 and MD-2, was described. Intracellular events following the formation of this receptor complex depend on different sets of adapters. An early response, which is dependent on MyD88 and MyD88-like adapter (Mal), leads to the activation of nuclear factor-kappaB (NF-kappaB). A later response to LPS makes use of TIR-domain-containing adapter-inducing interferon-beta (TRIF) and TRIF-related adapter molecule (TRAM), and leads to the late activation of NF-kappaB and IRF3, and to the induction of cytokines, chemokines, and other transcription factors. As LPS signal transduction is an area of intense research and rapid progress, this review is intended to sum up our present understanding of the events following LPS binding to TLR4, and we also attempt to create a model of the signalling pathways activated by LPS.
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PMID:Signal transduction by the lipopolysaccharide receptor, Toll-like receptor-4. 1537 75

Interferon regulatory factors (IRFs) are critical components of virus-induced immune activation and type I interferon regulation. IRF3 and IRF7 are activated in response to a variety of viruses or after engagement of Toll-like receptor (TLR) 3 and TLR4 by double-stranded RNA and lipopolysaccharide, respectively. The activation of IRF5, is much more restricted. Here we show that in contrast to IRF3 and IRF7, IRF5 is not a target of the TLR3 signaling pathway but is activated by TLR7 or TLR8 signaling. We also demonstrate that MyD88, interleukin 1 receptor-associated kinase 1, and tumor necrosis factor receptor-associated factor 6 are required for the activation of IRF5 and IRF7 in the TLR7 signaling pathway. Moreover, ectopic expression of IRF5 enabled type I interferon production in response to TLR7 signaling, whereas knockdown of IRF5 by small interfering RNA reduced type I interferon induction in response to the TLR7 ligand, R-848. IRF5 and IRF7, therefore, emerge from these studies as critical mediators of TLR7 signaling.
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PMID:The interferon regulatory factor, IRF5, is a central mediator of toll-like receptor 7 signaling. 1569 21

Dendritic cells (DC) produce interleukin-12 (IL-12) in response to Toll-like receptor (TLR) activation. Two major TLR signaling pathways participate in the response to pathogens: the nuclear factor-kappaB (NF-kappaB)-dependent pathway leading to inflammatory cytokine secretion including IL-12 and the interferon (IFN)-dependent pathway inducing type I IFN and IFN-regulated genes. Here we show that the two pathways cooperate and are likely both necessary for inducing an optimal response to pathogens. R-848/Resiquimod (TLR7 ligand in the mouse and TLR7/8 ligand in human) synergized with poly(I:C) (TLR3 ligand) or lipopolysaccharide (LPS; TLR4 ligand) in inducing high levels of bioactive IL-12p70 secretion and IFN-beta mRNA accumulation by mouse bone marrow-derived DC (BM-DC). Strikingly, IL-12p70 but not IL-12p40 secretion was strongly reduced in BM-DC from STAT1(-/-) and IFNAR(-/-) mice. STAT1 tyrosine-phosphorylation, IL-12p35, and IFN-beta mRNA accumulation were strongly inhibited in IFNAR(-/-) BM-DC activated with the TLR ligand combinations. Similar observation were obtained in human TLR8-expressing monocyte-derived DC (moDC) using neutralizing anti-IFNAR2 antibodies, although results also pointed to a possible involvement of IFN-lambda1 (also known as IL-29). This suggests that TLR engagement on DC induces endogenous IFNs that further synergize with the NF-kappaB pathway for optimal IL-12p70 secretion. Moreover, analysis of interferon regulatory factors (IRF) regulation in moDC suggests a role for IRF7/8 in mediating IRF3-independent type I IFN and possibly IL-12p35 synthesis in response to TLR7/8.
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PMID:A type I interferon autocrine-paracrine loop is involved in Toll-like receptor-induced interleukin-12p70 secretion by dendritic cells. 1585 85

Here we identify Viperin as a highly inducible gene in response to lipopolysaccharide (LPS), double-stranded RNA (poly(I-C)) or Sendai virus (SV). The only known function of Viperin relates to its ability to inhibit human Cytomegalovirus replication. Very little data are available on the regulation of this gene. In silico analysis of the promoter identified two interferon (IFN)-stimulated response elements (ISRE), which in other genes bind IRF3 or the IFN-stimulated gene factor-3 (ISGF3) complex. LPS and poly(I-C) induce very high levels of Viperin in wild type cells but not in cells deficient in TRIF, TBK1, IRF3, or the type I IFNalpha/betaR. SV-induced Viperin gene expression was mediated independently of Toll-like receptor (TLR) signaling by retinoic acid-inducible gene (RIG-I) and the downstream adapter, mitochondrial anti-viral signaling (MAVS). Virus-induced Viperin expression was not attenuated in macrophages deficient in either TBK1 or IKKepsilon alone. Moreover, IRF3-deficient, but not IFNalpha/betaR deficient, macrophages still induced Viperin in response to SV. Promoter reporter studies combined with DNA immunoprecipitation assays identified the ISGF3 complex as the key regulator of Viperin gene expression. Moreover, positive regulatory domain I-binding factor 1 (PRDI-BF1, also called BLIMP1) binds the ISRE sites and competes with ISGF3 binding in a virus inducible manner to inhibit Viperin transcription. Collectively, these studies identify Viperin as a tightly regulated ISGF3 target gene, which is counter-regulated by PRDI-BF1.
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PMID:Toll-like receptor-dependent and -independent viperin gene expression and counter-regulation by PRDI-binding factor-1/BLIMP1. 1684 20

Type I interferon gene induction relies on IKK-related kinase TBK1 and IKKepsilon-mediated phosphorylations of IRF3/7 through the Toll-like receptor-dependent signaling pathways. The scaffold proteins that assemble these kinase complexes are poorly characterized. We show here that TANK/ITRAF is required for the TBK1- and IKKepsilon-mediated IRF3/7 phosphorylations through some Toll-like receptor-dependent pathways and is part of a TRAF3-containing complex. Moreover, TANK is dispensable for the early phase of double-stranded RNA-mediated IRF3 phosphorylation. Interestingly, TANK is heavily phosphorylated by TBK1-IKKepsilon upon lipopolysaccharide stimulation and is also subject to lipopolysaccharide- and TBK1-IKKepsilon-mediated Lys(63)-linked polyubiquitination, a mechanism that does not require TBK1-IKKepsilon kinase activity. Thus, we have identified TANK as a scaffold protein that assembles some but not all IRF3/7-phosphorylating TBK1-IKKepsilon complexes and demonstrated that these kinases possess two functions, namely the phosphorylation of both IRF3/7 and TANK as well as the recruitment of an E3 ligase for Lys(63)-linked polyubiquitination of their scaffold protein, TANK.
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PMID:Lipopolysaccharide-mediated interferon regulatory factor activation involves TBK1-IKKepsilon-dependent Lys(63)-linked polyubiquitination and phosphorylation of TANK/I-TRAF. 1782 24

Various receptors on cell surface recognize specific extracellular molecules and trigger signal transduction altering gene expression in the nucleus. Gain or loss-of-function mutations of one molecule have shown to affect alternative signaling pathways with a poorly understood mechanism. In Toll-like receptor (TLR) 4 signaling, which branches into MyD88- and TRAM-dependent pathways upon lipopolysaccharide (LPS) stimulation, we investigated the gain or loss-of-function mutations of MyD88. We predict, using a computational model built on the perturbation-response approach and the law of mass conservation, that removal and addition of MyD88 in TLR4 activation, enhances and impairs, respectively, the alternative TRAM-dependent pathway through signaling flux redistribution (SFR) at pathway branches. To verify SFR, we treated MyD88-deficient macrophages with LPS and observed enhancement of TRAM-dependent pathway based on increased IRF3 phosphorylation and induction of Cxcl10 and Ifit2. Furthermore, increasing the amount of MyD88 in cultured cells showed decreased TRAM binding to TLR4. Investigating another TLR4 pathway junction, from TRIF to TRAF6, RIP1 and TBK1, the removal of MyD88-dependent TRAF6 increased expression of TRAM-dependent Cxcl10 and Ifit2. Thus, we demonstrate that SFR is a novel mechanism for enhanced activation of alternative pathways when molecules at pathway junctions are removed. Our data suggest that SFR may enlighten hitherto unexplainable intracellular signaling alterations in genetic diseases where gain or loss-of-function mutations are observed.
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PMID:Signaling flux redistribution at toll-like receptor pathway junctions. 1892 10

Toll-like receptors (TLRs) are vital in the induction of innate immune responses. The microbial components trigger the activation of the myeloid differential factor 88 (MyD88)- and toll-interleukin-1 receptor domain-containing adapter inducing interferon-beta (TRIF)-dependent downstream TLR signaling pathways. Guggulsterone, which has been used for centuries to treat many chronic diseases, inhibits the MyD88-dependent pathway by inhibiting the activity of inhibitor-kappaB kinase. However, it is not known whether guggulsterone inhibits the TRIF-dependent pathway. Presently, we sought to identify the molecular targets of guggulsterone in this pathway. Guggulsterone inhibited nuclear factor-kappaB and IRF3 activation induced by lipopolysaccharide or poly[I:C] and activation of IRF3 induced by the overexpression of TRIF, TBK1 or constitutively active IRF3. Guggulsterone also suppressed the lipopolysaccharide-induced phosphorylation of IRF3. These results suggest that guggulsterone can modulate both MyD88- and TRIF-dependent signaling pathways of TLRs leading to decreased inflammatory gene expression.
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PMID:Guggulsterone suppresses the activation of transcription factor IRF3 induced by TLR3 or TLR4 agonists. 1900 Jul 89

Interferon regulatory factor (IRF)3 is critical for the transcriptional induction of chemokines and cytokines during viral or bacterial invasion. The kinases Tank binding kinase (TBK)1 and Ikappa B kinase (IKK)epsilon can phosphorylate the C-terminal part of IRF3 and play important roles in IRF3 activation. In this study, we show that another kinase, c-Jun-NH(2)-terminal kinase (JNK), phosphorylates IRF3 on its N-terminal serine 173 residue, and TAK1 can stimulate IRF3 phosphorylation via JNK. JNK specific inhibitor SP600125 inhibits the N-terminal phosphorylation without affecting the C-terminal phosphorylation. In addition, IRF3-mediated gene expressions on lipopolysaccharide (LPS) or polyinosinic-cytidylic acid (polyI:C) treatment are severely impaired by SP600125, as well as for reporter gene assay of IRF3 activation. Knockdown of TAK1 further confirmed these observations. Interestingly, constitutive active IRF3(5D) can be inhibited by SP600125; JNK1 can synergize the action of IRF3(5D), but not the S173A-IRF3(5D) mutant. More importantly, polyI:C failed to induce the phosphorylation of mutant S173A and SP600125 dramatically abrogated IRF3 phosphorylation and dimerization that was stimulated by polyI:C. Thus, this study demonstrates that the TAK1-JNK cascade is required for IRF3 function, in addition to TBK1/IKKvarepsilon, uncovering a new mechanism for mitogen-activated protein (MAP) kinase to regulate the innate immunity.
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PMID:The TAK1-JNK cascade is required for IRF3 function in the innate immune response. 1915 95


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