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)

Members of the nuclear factor kappa B (NF-kappaB) family of dimeric transcription factors (TFs) regulate expression of a large number of genes involved in immune responses, inflammation, cell survival, and cancer. NF-kappaB TFs are rapidly activated in response to various stimuli, including cytokines, infectious agents, and radiation-induced DNA double-strand breaks. In nonstimulated cells, some NF-kappaB TFs are bound to inhibitory IkappaB proteins and are thereby sequestered in the cytoplasm. Activation leads to phosphorylation of IkappaB proteins and their subsequent recognition by ubiquitinating enzymes. The resulting proteasomal degradation of IkappaB proteins liberates IkappaB-bound NF-kappaB TFs, which translocate to the nucleus to drive expression of target genes. Two protein kinases with a high degree of sequence similarity, IKKalpha and IKKbeta, mediate phosphorylation of IkappaB proteins and represent a convergence point for most signal transduction pathways leading to NF-kappaB activation. Most of the IKKalpha and IKKbeta molecules in the cell are part of IKK complexes that also contain a regulatory subunit called IKKgamma or NEMO. Despite extensive sequence similarity, IKKalpha and IKKbeta have largely distinct functions, due to their different substrate specificities and modes of regulation. IKKbeta (and IKKgamma) are essential for rapid NF-kappaB activation by proinflammatory signaling cascades, such as those triggered by tumor necrosis factor alpha (TNFalpha) or lipopolysaccharide (LPS). In contrast, IKKalpha functions in the activation of a specific form of NF-kappaB in response to a subset of TNF family members and may also serve to attenuate IKKbeta-driven NF-kappaB activation. Moreover, IKKalpha is involved in keratinocyte differentiation, but this function is independent of its kinase activity. Several years ago, two protein kinases, one called IKKepsilon or IKK-i and one variously named TBK1 (TANK-binding kinase), NAK (NF-kappaB-activated kinase), or T2K (TRAF2-associated kinase), were identified that exhibit structural similarity to IKKalpha and IKKbeta. These protein kinases are important for the activation of interferon response factor 3 (IRF3) and IRF7, TFs that play key roles in the induction of type I interferon (IFN-I). Together, the IKKs and IKK-related kinases are instrumental for activation of the host defense system. This Review focuses on the functions of IKK and IKK-related kinases and the molecular mechanisms that regulate their activities.
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PMID:Regulation and function of IKK and IKK-related kinases. 1704 24

Viral infection and type I interferon have been implicated in the pathogenesis of biliary atresia (BA), but the expression of toll-like receptors (TLRs) that recognize viruses, as well as of type 1 interferon specific signaling molecules are still unknown in BA. Fresh liver tissues were obtained from patients in early and late stage of BA and from patients with choledochal cyst (CC), as well as from normal controls receiving liver resection for benign lesion other than cholestasis or fibrosis. Archived liver tissues from patients with neonatal hepatitis (NH) were obtained for immunohistochemical studies. TLR2, 3, 4, 7 and 9 that recognized Gram-positive bacteria, double-stranded RNA virus, lipopolysaccharide, single-stranded RNA virus and DNA virus, respectively, were studied. Real-time quantitative reverse transcription polymerase chain reaction (QRT-PCR) was used to quantitate TLR, type I interferon specific molecule MxA, interleukin-6 (IL-6) and IL-8 mRNA expression and immunohistochemistry for TLR 7 and MxA protein staining. These results show that there were significantly higher TLR7 and lower TLR3 and TLR9 mRNA expression in early stage of BA than in CC. MxA mRNA expression was also significantly higher in early stage of BA and in CC than in late stage of BA. Immunoreactive TLR7 and MxA staining was higher in early stage of BA than in late stage of BA, NH and CC, which was associated with significantly higher IL-8 mRNA expression in BA than in CC. The results implicate involvement of TLRs, particularly TLR7, and type 1 specific interferon signaling in the pathogenesis of BA, especially in early stage, which is associated with upregulation of inflammatory cytokines IL-8.
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PMID:Expression of toll-like receptors and type 1 interferon specific protein MxA in biliary atresia. 1707 76

Toll-like receptor 4 (TLR4) initiates both myeloid differentiation factor 88 (MyD88)-dependent and Toll/interleukin (IL)-1R domain-containing adapter, inducing interferon (IFN)-beta-dependent signaling, leading to production of proinflammatory mediators and type I interferon (IFN) to eliminate pathogens. However, uncontrolled TLR4 activation may contribute to pathogenesis of autoimmune and inflammatory diseases. TLR4 is transported from the plasma membrane to the endosome for ubiqutination and to the lysosome for degradation, and downregulation of TLR4 expression or promotion of TLR4 degradation are important ways for negative regulation of TLR4 signaling. We previously identified a lysosome-associated small guanosine triphosphatase (GTPase) Rab7b that may be involved in lysosomal trafficking and degradation of proteins. Here we demonstrate that Rab7b can negatively regulate lipopolysaccharide (LPS)-induced production of tumor necrosis factor (TNF)-alpha, IL-6, nitric oxide, and IFN-beta, and potentiate LPS-induced activation of mitogen-activated protein kinase, nuclear factor kappaB, and IFN regulatory factor 3 signaling pathways in macrophages by promoting the degradation of TLR4. Rab7b is localized in LAMP-1-positive subcellular compartments and colocalized with TLR4 after LPS treatment and can decrease the protein level of TLR4. Our findings suggest that Rab7b is a negative regulator of TLR4 signaling, potentially by promoting the translocation of TLR4 into lysosomes for degradation.
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PMID:Lysosome-associated small Rab GTPase Rab7b negatively regulates TLR4 signaling in macrophages by promoting lysosomal degradation of TLR4. 1739 80

IRAK4 is a member of IL-1 receptor (IL-1R)-associated kinase (IRAK) family and has been shown to play an essential role in Toll-like receptor (TLR)-mediated signaling. We recently generated IRAK4 kinase-inactive knock-in mice to examine the role of kinase activity of IRAK4 in TLR-mediated signaling pathways. The IRAK4 kinase-inactive knock-in mice were completely resistant to lipopolysaccharide (LPS)- and CpG-induced shock, due to impaired TLR-mediated induction of proinflammatory cytokines and chemokines. Although inactivation of IRAK4 kinase activity did not affect the levels of TLR/IL-1R-mediated nuclear factor kappaB activation, a reduction of LPS-, R848-, and IL-1-mediated mRNA stability contributed to the reduced cytokine and chemokine production in bone marrow-derived macrophages from IRAK4 kinase-inactive knock-in mice. Both TLR7- and TLR9-mediated type I interferon production was abolished in plasmacytoid dendritic cells isolated from IRAK4 knock-in mice. In addition, influenza virus-induced production of interferons in plasmacytoid DCs was also dependent on IRAK4 kinase activity. Collectively, our results indicate that IRAK4 kinase activity plays a critical role in TLR-dependent immune responses.
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PMID:A critical role for IRAK4 kinase activity in Toll-like receptor-mediated innate immunity. 1747 Jun 42

Invariant natural killer T (iNKT) cells are a subset of innate lymphocytes that recognize lipid antigens in the context of CD1d and mediate potent immune regulatory functions via the rapid production of interferon-gamma (IFN-gamma) and interleukin-4 (IL-4). We investigated whether diverse Toll-like receptor (TLR) signals in myeloid dendritic cells (DCs) could differentially stimulate iNKT cells. Together with the lipopolysaccharide-detecting receptor TLR4, activation of the nucleic acid sensors TLR7 and TLR9 in DCs were particularly potent in stimulating iNKT cells to produce IFN-gamma, but not IL-4. iNKT cell activation in response to TLR9 stimulation required combined synthesis of type I interferon and de novo production of charged beta-linked glycosphingolipid(s) by DCs. In addition, DCs stimulated via TLR9 activated both iNKT cells and NK cells in vivo and protected mice against B16F10-induced melanoma metastases. These data underline the role of TLR9 in iNKT cell activation and might have relevance to infectious diseases and cancer.
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PMID:Activation of invariant NKT cells by toll-like receptor 9-stimulated dendritic cells requires type I interferon and charged glycosphingolipids. 1795 5

Activation of the mitogen-activated protein kinases (MAPKs) and nuclear factor kappaB (NF-kappaB) cascades after Toll-like receptor (TLR) stimulation contributes to innate immune responses. Signal regulatory protein (SIRP) alpha, a member of the SIRP family that is abundantly expressed in macrophages, has been implicated in regulating MAPK and NF-kappaB signaling pathways. In addition, SIRPalpha can negatively regulate the phagocytosis of host cells by macrophages, indicating an inhibitory role of SIRPalpha in innate immunity. We provide evidences that SIRPalpha is an essential endogenous regulator of the innate immune activation upon lipopolysaccharide (LPS) exposure. SIRPalpha expression was promptly reduced in macrophages after LPS stimulation. The decrease in SIRPalpha expression levels was required for initiation of LPS-induced innate immune responses because overexpression of SIRPalpha reduced macrophage responses to LPS. Knockdown of SIRPalpha caused prolonged activation of MAPKs and NF-kappaB pathways and augmented production of proinflammatory cytokines and type I interferon (IFN). Mice transferred with SIRPalpha-depleted macrophages were highly susceptible to endotoxic shock, developing multiple organ failure and exhibiting a remarkable increase in mortality. SIRPalpha may accomplish this mainly through its association and sequestration of the LPS signal transducer SHP-2. Thus, SIRPalpha functions as a biologically important modulator of TLR signaling and innate immunity.
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PMID:LPS-induced down-regulation of signal regulatory protein {alpha} contributes to innate immune activation in macrophages. 1795 68

Phosphatidylinositol-3-phosphate kinase (PI3K) has been reported to exhibit anti-inflammatory roles as a negative modulator of the NF-kappaB pathway (MyD88- and Mal-dependent) triggered upon Toll-like receptor (TLR)4 activation by lipopolysaccharide (LPS). Here, we investigated the role of PI3K on the TLR4-dependent, MyD88-independent signaling cascade which is activated in macrophages infected by Vesicular Stomatitis Virus (VSV) and leads to interferon production, thus conferring antiviral protection. We show that VSV induces TLR4 (and CD14)-dependent Akt phosphorylation. We observed hypersusceptibility to viral infections after pharmacological inactivation of the PI3K pathway in macrophages, which indicates that normal PI3K functions are critical for type I interferon synthesis and viral resistance. Conversely, we noticed increased resistance in macrophages isolated from genetically modified mice in which the PI3K pathway is constitutively active. Our data, which demonstrate that PI3K-Akt axis is an important component of the TLR4-dependent antiviral mechanism, also indicate that pharmacological modulation of this pathway to regulate the inflammatory response could promote viral susceptibility.
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PMID:TLR4/CD14-mediated PI3K activation is an essential component of interferon-dependent VSV resistance in macrophages. 1833 26

Type 1 diabetes (T1D) is a chronic disorder that results from autoimmune destruction of the insulin-producing pancreatic beta cell. The nonobese diabetic (NOD) mouse is a model of the human autoimmune disease T1D. Soluble immune response suppressor (SIRS) is a nonspecific protein suppressor of immune response produced by immunomodulatory T cells stimulated by type I interferon (IFN). SIRS inhibits antibody responses in vivo, lipopolysaccharide (LPS)-induced fever, and delayed-type hypersensitivity (DTH) responses. Previous investigators have isolated the N-terminal sequence of SIRS protein consisting of 21 amino acids. Mice ingesting 1 microg SIRS peptide 1-21 showed significant delayed onset of T1D and a decreased frequency of T1D compared with mock-fed and 10-microg-fed mice and a significant decrease in islet inflammation. There were significant decreases in islet lymphocyte chemokine production of granulocyte-macrophage colony-stimulating factor (GM-CSF), macrophage inflammatory protein-1 gamma (MIP-1 gamma), regulated upon activation, normal T cell-expressed, and presumably secreted (RANTES), and stromal cell-derived factor-1 (SDF-1) in the SIRS-fed mice, factors important in migration of inflammatory cell into the islets. Ingested (oral) SIRS peptide inhibits clinical T1D by decreasing target organ cellular migration of islet destructive populations by suppression of islet lymphocyte chemokine secretion.
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PMID:Ingested (oral) SIRS peptide 1-21 suppresses type 1 diabetes in NOD mice. 1837 Aug 69

Dendritic cell maturation is the process by which immature dendritic cells differentiate into fully competent antigen-presenting cells that initiate T cell responses. Although some mechanistic aspects of DC maturation have begun to be characterised, very little is known about the genetic events regulating the ubiquitin-proteasome system which plays a key role at various levels of the immune response. Therefore, we here investigated the expression of more than 1000 genes related to the ubiquitin-proteasome system in maturing dendritic cells following various stimuli and identified a specific set of transcripts induced by lipopolysaccharide and/or Poly(I:C) which is largely distinct from that induced by CD40 ligand or pro-inflammatory cytokines. This group of genes was dependent on a type I interferon autocrine loop and included E1 and E2 enzymes, E3-ligases, de-ubiquitylating enzymes, proteasome components as well as the ubiquitin-like modifiers ISG15 and FAT10. We further demonstrate that the increased expression of the E2 enzyme UBE2L6 (UbcH8) is required for efficient antigen cross-presentation by dendritic cells. In summary, our data underline the importance of remodelling the ubiquitin-proteasome system for dendritic cell function.
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PMID:Maturation of human dendritic cells is accompanied by functional remodelling of the ubiquitin-proteasome system. 1902 97

Gram-negative bacterial infections, unlike viral infections, do not typically protect against subsequent viral infections. This is puzzling given that lipopolysaccharide (LPS) and double-stranded (ds) RNA both activate the TIR domain-containing adaptor-inducing interferon beta (TRIF) pathway and, thus, are both capable of eliciting an antiviral response by stimulating type I interferon (IFN) production. We demonstrate herein that SH2-containing inositol-5'-phosphatase (SHIP) protein levels are dramatically increased in murine macrophages via the MyD88-dependent pathway, by up-regulating autocrine-acting transforming growth factor-beta (TGFbeta). The increased SHIP then mediates, via inhibition of the phosphatidylinositol-3-kinase (PI3K) pathway, cytosine-phosphate-guanosine (CPG)- and LPS-induced tolerance and cross-tolerance and restrains IFN-beta production induced by a subsequent exposure to LPS or dsRNA. Intriguingly, we found, using isoform-specific PI3K inhibitors, that LPS- or cytosine-phosphate-guanosine-induced interleukin-6 (IL-6) is positively regulated by p110alpha, -gamma, and -delta but negatively regulated by p110beta. This may explain some of the controversy concerning the role of PI3K in Toll-like receptor-induced cytokine production. Consistent with our in vitro findings, SHIP(-/-) mice overproduce IFN-beta in response to LPS, and this leads to antiviral hypothermia. Thus, up-regulation of SHIP in response to Gram-negative bacterial infections probably explains the inability of such infections to protect against subsequent viral infections.
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PMID:SHIP prevents lipopolysaccharide from triggering an antiviral response in mice. 1913 77


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