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)

Premature infants with placental infection and adult stroke patients with fever have worse outcomes following intracerebral hemorrhage (ICH). We hypothesized that immune pre-activation would aggravate brain injury in mouse brain following ICH. The immune system of 2-day, 10-day and 7-week young adult CD1 mice was stimulated by intraperitoneal injection of concanavalin A (ConA), lipopolysaccharide (LPS) or polyinosinic-polycytidilic acid (PolyI:C) 12 h prior to intracerebral injection of blood. Two days later, brain damage and inflammation were worse in 2-day mice that had received LPS. The other agents had less consistent effects in 2-day mice. Brain damage in young adults was aggravated less after immune stimulation. These data suggest that immune pre-activation modifies hemorrhagic brain injury in immature mouse brain.
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PMID:Immune pre-activation exacerbates hemorrhagic brain injury in immature mouse brain. 1596 38

Interleukin-12 (IL-12) is a heterodimeric cytokine produced by dendritic cells (DCs) in response to Toll-like receptor (TLR) ligation. While the mechanisms regulating IL-12p40 chain gene expression are well characterized, molecular events involved in IL-12p35 chain gene activation remain to be clarified. Since IL-12p35 mRNA was induced in human DCs activated through TLR3 or TLR4 but not TLR2, we investigated the potential role of interferon regulatory factor 3 (IRF-3) in IL-12p35 gene transactivation. First, a binding site for IRF-3 named interferon-stimulated response element-1 (ISRE-1) was identified in the human IL-12p35 promoter region between nucleotides -251 and -240. The ISRE-1 site was required for IL-12p35 gene activation in RAW 264.7 cells stimulated by lipopolysaccharide (LPS) or PolyI:C. Ectopic expression of IRF-3 was found to up-regulate IL-12p35 gene activation in the same system. Furthermore, chromatin immunoprecipitation (ChIP) studies demonstrated that IRF-3 is recruited to ISRE-1 site in TLR4- or TLR3-stimulated human DCs. Finally, experiments on DCs from IRF-3-deficient mice established that TLR4-induced IL-12p35 mRNA and IL-12p70 synthesis are impaired in absence of IRF-3. We conclude that IRF-3 binds to a critical cis-acting element in the IL-12p35 gene promoter and thereby represents a key factor for the induction of IL-12p70 synthesis in DCs.
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PMID:Interferon regulatory factor 3 is involved in Toll-like receptor 4 (TLR4)- and TLR3-induced IL-12p35 gene activation. 1621 95

Monocyte-derived dendritic cells (MoDCs) in clinical use for cancer immunotherapy are ideally generated in serum-free medium (SFM) with inclusion of a suitable maturation factor toward the end of the incubation period. Three good manfacturing practice (GMP) grade SFMs (AIM-V, X-VIVO 15, and X-VIVO 20) were compared with RPMI-1640, supplemented with 10% fetal bovine serum or 10% human serum. DCs generated for 7 days in SFM were less mature and secreted less interleukin (IL) 12p70 and IL-10 than DCs generated in 10% serum. DC yield was comparable in SFMs, and a greater proportion of cells was viable after maturation. Toll-like receptor (TLR) ligands were compared for their ability to induce cytokine secretion under serum-free conditions in the presence of interferon (IFN) gamma. With the exception of Poly I:C, TLR ligands stimulated high levels of IL-10 secretion. High levels of IL-12p70 were induced by two TLR4-mediated stimuli, lipopolysaccharide and Ribomunyl, a clinical-grade bacterial extract. When T-cell responses were compared in allogeneic mixed leukocyte reaction, DCs stimulated with Ribomunyl induced higher levels of IFNgamma than DCs stimulated with the cytokine cocktail: tumor necrosis factor-alpha, IL-1beta, IL-6, and prostaglandin E2. In the presence of IL-10 neutralizing antibodies, DC IL-12p70 production and T-cell IFNgamma were increased in vitro. Similarly, DCs stimulated with Ribomunyl, IFNgamma, and anti-IL-10 induced high levels of tetanus toxoid-specific T-cell proliferation and IFNgamma secretion. Thus, MoDCs generated in SFM efficiently stimulate T-cell IFNgamma production after maturation in the presence of a clinical-grade TLR4 agonist and IL-10 neutralization.
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PMID:Generation and maturation of dendritic cells for clinical application under serum-free conditions. 1622 78

We demonstrate, by 5-bromo-2'-deoxyuridine (BrdU) tracing, the effects of peripheral administration of toll-like receptor (TLR) and NOD2 ligands (stimulators of the innate immune system) on the proliferation of spinal cord cells. Bolus injection of phosphorothioate oligonucleotides containing CpG motifs had no prominent effects on spinal cord neural progenitor cell proliferation, whereas single intraperitoneal injection of polyinosine-polycytidylic acid (Poly I:C, TLR3 ligand), lipopolysaccharide (LPS, TLR4 ligand), R848 (TLR7/8 ligand), or N-acetylmuramyldipeptide (MDP, Nod2 ligand) temporarily increased the number of BrdU(+) cells in the spinal cord. For Poly I:C- or R848-treated groups, the density of BrdU cells reached maximal levels on days 2 to 3 postinjection and then rapidly declined to baseline levels. Only a few of the proliferating cells were of microglial origin, but BrdU(+)/nestin(+) cells were found, suggestive of a proliferation of local progenitor cells. In addition, stimulation of cell proliferation correlated with activation of the innate immune system, that is, microglial cells. Interestingly, activation and cell proliferation was inhibited by corticosteroid dexamethasone but not by indomethacin. These findings suggest an intricate interaction of phylogenetically ancient cellular processes of the innate immune system and regeneration.
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PMID:TLR and NOD2 ligands induce cell proliferation in the rat intact spinal cord. 1625 93

This study demonstrates that pretreatment with polyinosinic-polycytidylic acid (poly I:C) significantly decreased the mortality and liver injury caused by injection of lipopolysaccharide (LPS) in the presence of d-galactosamine (d-GalN) in C57BL/6 mice. Depletion of natural killer, natural killer T, and T cells did not change the protective effect of poly I:C on LPS/d-GalN-induced liver injury in vivo. However, depletion of macrophages abolished LPS/d-GalN-induced fulminant hepatitis, which could be restored by adoptive transfer of macrophages but not by transfer of poly I:C-treated macrophages. Treatment with poly I:C down-regulated the expression of the toll-like receptor 4 (TLR4) on macrophages and reduced the sensitivity of macrophages (Kupffer cells and peritoneal macrophages from C57BL/6 mice, or RAW264.7 cells) to LPS stimulation. Poly I:C pretreatment also impaired the signaling of mitogen-activated protein kinases and NF-kappaB induced by LPS in RAW264.7 cells. Blockade of TLR3 with a TLR3 antibody abolished poly I:C down-regulation of TLR4 expression and LPS stimulation of TNF-alpha production in RAW264.7 cells. Taken together, our findings suggest that activation of TLR3 by its ligand, poly I:C, induced LPS tolerance by down-regulation of TLR4 expression on macrophages.
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PMID:Toll-like receptor 3 ligand attenuates LPS-induced liver injury by down-regulation of toll-like receptor 4 expression on macrophages. 1628 79

Maternal inflammation plays a role in the etiology of certain neurodevelopmental disorders including autism and schizophrenia. Because maternal inflammation can lead to activation of fetal microglia, we have examined effects of inflamed microglia on cultured neural progenitors from rat embryonic septal region and basal forebrain. These cells give rise to cholinergic neurons projecting to cortex and hippocampus. Microglia stimulated with lipopolysaccharide (LPS), peptidoglycan, Poly I:C and CD154 produce conditioned media (CM) that promotes excessive numbers of cholinergic neurons and levels of choline acetyltransferase (ChAT) activity 6-8 times that of untreated cultures. Expression of the neural-specific transcription factor MATH1 increases substantially within 1 h of plating in LPS-CM. Untreated cultures do not attain equivalent levels until 6 h. By contrast, expression of glial-related transcription factors in LPS-CM-treated cultures never attains the elevated levels of untreated cultures. LPS-CM-treated clones derived from individual progenitors labeled with a LacZ-expressing retrovirus showed >2.5-fold increase in the percentage of cholinergic cells compared with untreated clones. Thus, CM from activated microglia prompts excess cholinergic differentiation from undifferentiated progenitors suggesting that microglial inflammation during critical stages can lead to aberrant brain development.
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PMID:Toll-like receptor ligands and CD154 stimulate microglia to produce a factor(s) that promotes excess cholinergic differentiation in the developing rat basal forebrain: implications for neurodevelopmental disorders. 1721 Nov 34

ISG15 is one of the most strongly induced genes upon viral infection, interferon (IFN) stimulation, and lipopolysaccharide (LPS) stimulation, and only one copy has been found in mammals so far. Here two fish ISG15 genes, termed CaISG15-1 and CaISG15-2, have been cloned and sequenced from UV-inactivated GCHV (grass carp haemorrhagic virus)-infected and IFN-produced CAB cells (crucian carp Carassius auratus blastulae embryonic cells) by suppression subtractive hybridization. The full-length cDNA sequences of two crucian carp ISG15 encode a 155-amino-acid protein and a 161-amino-acid protein, both of which show 78.9% identity overall and possess the characteristic structures of mammalian ISG15 proteins including two tandem ubiquitin-like domains and the C-terminal canonical LRLRGG motif. In CAB cells treated with different stimuli including active virus, UV-inactivated GCHV and IFN containing supernatant (ICS), the expression of both CaISG15-1 and CaISG15-2 was upregulated but displayed different kinetics. Poly I:C and LPS were also able to induce an increase in mRNA for both genes. In CAB cells responsive to active GCHV, UV-inactivated GCHV, CAB ICS, Poly I:C and LPS, CaISG15-1 was upregulated more significantly than CaISG15-2. These results suggest that there are two ISG15 homologues in crucian carp, both of which might play distinct roles in innate immunity against viral and bacterial infection.
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PMID:Identification and characterization of two homologues of interferon-stimulated gene ISG15 in crucian carp. 1735 Aug 61

For predominant abundance with liver-specific Kupffer cells, natural killer (NK) cells, and natural killer T (NKT) cells and their rapid responses to several stimuli, the liver is considered as an organ with innate immune features. In contrast to their roles in the defense of many infectious agents like hepatitis viruses and parasites, hepatic innate immune cells are also involved in the immunopathogenesis of human clinical liver diseases and several murine hepatitis models such as concanavalin A (Con A), lipopolysaccharide (LPS), or polyinosinic-polycytidylic acid (Poly I:C)-induced liver injury. In this review, the destructive roles of NK cells, NKT cells and Kupffer cells in the processes of immune-mediated liver injury and regeneration will be discussed, and some putative mechanisms involving the impairment of liver regeneration caused by activated hepatic innate immune cells are also proposed.
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PMID:The roles of innate immune cells in liver injury and regeneration. 1776 14

Human cytomegalovirus (HCMV) can be acquired sexually and is shed from the genital tract. Cross-sectional studies in women show that changes in genital tract microbial flora affect HCMV infection and/or shedding. Since genital microbial flora may affect HCMV infection or replication by stimulating cells through Toll-like receptors (TLR), we assessed the effects of defined TLR-ligands on HCMV replication in foreskin fibroblasts and ectocervical tissue. Poly I:C (a TLR3-ligand) and lipopolysaccharide (LPS, a TLR4-ligand) inhibited HCMV and induced secretion of IL-8 and Interferon-beta (IFNbeta) in both foreskin fibroblasts and ectocervical tissue. The anti-HCMV effect was reversed by antibody to IFNbeta. CpG (TLR9 ligand) and lipoteichoic acid (LTA, TLR2 ligand) also inhibited HCMV infection in ectocervical tissue and this anti-HCMV effect was also reversed by anti-IFNbeta antibody. In contrast, LTA and CpG did not inhibit HCMV infection in foreskin fibroblasts. This study shows that TLR ligands induce an HCMV-antiviral effect that is mediated by IFNbeta suggesting that changes in genital tract flora may affect HCMV infection or shedding by stimulating TLR. This study also contrasts the utility of two models that can be used for assessing the interaction of microbial flora with HCMV in the genital tract. Clear differences in the response to different TLR ligands suggests the explant model more closely reflects in vivo responses to genital infections.
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PMID:Differential inhibition of human cytomegalovirus (HCMV) by toll-like receptor ligands mediated by interferon-beta in human foreskin fibroblasts and cervical tissue. 1805 51

Our understanding of the innate immune response in the horse has been limited by a lack of definitive data concerning cell signaling in response to microbial products. Toll-like receptors (TLRs) recognize conserved molecular motifs of microbes and elicit immune responses through their coupling with intracellular adaptor molecules, particularly MyD88 and TRIF. To provide a more definitive characterization of TLR signaling in the horse, the objectives of this study were to: (1) characterize the responses of equine monocytes to TLR ligands that signal through MyD88, TRIF or both in other species, and (2) determine the profiles of gene expression initiated utilizing these adaptor molecules. Monocytes were used to establish concentration response curves for Escherichia coli lipopolysaccharide (LPS; TLR4 ligand) and N-palmitoyl-S-[2,3-bis(palmitoyloxy)-(2RS)-propyl]-[R]-cysteinyl-[S]-seryl-[S]-lysyl-[S]-lysyl-[S]-lysyl-[S]-lysine x 3 HCl (Pam(3)CSK(4); TLR2 ligand) based on expression of procoagulant activity (PCA) and production of tumor necrosis factor-alpha (TNF-alpha); effects of polyinosine-polycytidylic acid (Poly I:C; TLR3 ligand) were determined by quantifying expression of mRNA for interferon-beta (IFN-ss). Expression of genes associated with the MyD88- (TNF-alpha, IL-1ss, IL-6 and IL-10) and TRIF-dependent pathways (IFN-ss, IP-10, RANTES and TRAF1) were measured at intervals spanning 20 h. LPS and Pam(3)CSK(4) induced significantly higher expression of TNF-alpha, IL-1ss, and IL-10 than did Poly I:C. Poly I:C induced significantly higher expression of IFN-ss, IP-10 and RANTES than did either the TLR2 or TLR4 ligands. High concentrations of E. coli LPS did not significantly increase expression of genes associated with the TRIF-dependent pathway. The results of this study suggest that equine monocytes utilize a common intracellular pathway in response to TLR2 and TLR4 ligands, but a distinct pathway in response to TLR3 ligands.
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PMID:Differential induction of MyD88- and TRIF-dependent pathways in equine monocytes by Toll-like receptor agonists. 1901 56


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