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)

Flagellin, the principal component of bacterial flagella, is a ligand for Toll-like receptor 5 (TLR5) or TLR11 and contributes to systemic inflammation during sepsis through activation of dendritic cells (DCs) and other cells of the innate immune system. Here, we report that flagellin and the TLR4 ligand, lipopolysaccharide (LPS), induced phenotypic and functional maturation of murine bone marrow-derived DCs and enhanced DC accumulation in the draining popliteal lymph node following their footpad injection. It is interesting that flagellin injection enhanced myeloid (CD8alpha(-1)) and plasmacytoid (plasmacytoid DC antigen(+) B220(+)) DC subsets, whereas LPS only increased myeloid DCs in the draining lymph node. In addition, the footpad injection of flagellin or LPS induced significant CD4(+) T cell activation in the draining popliteal lymph node, as judged by increased CD69 or CD25 expression. We illustrate, for the first time, that flagellin also increases natural killer (NK) cell number and activation status in the draining lymph node after footpad injection. Using coculture with enriched carboxy-fluorescein diacetate succinimidyl ester-labeled NK cells, flagellin-treated DCs induce significant NK cell proliferation and activation. In fact, direct treatment of NK cells with flagellin induces a greater increase in cell proliferation than treatment with LPS. In contrast, flagellin treatment of NK cells was not a strong inducer of interferon-gamma (IFN-gamma) production, indicating that NK cell proliferation and IFN-gamma production may be regulated differentially. These data suggest that flagellin is a capable maturation agent for murine myeloid-derived DCs, and flagellin-activated DCs and flagellin itself are potent inducers of NK cell proliferation.
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PMID:Flagellin enhances NK cell proliferation and activation directly and through dendritic cell-NK cell interactions. 1603 15

We have previously characterized a new type of stem cell from human peripheral blood, termed fibroblast-like macrophage (f-Mphi). Here, using umbilical cord blood as a source, we identified cells with similar characteristics including expression of surface markers (CD14, CD34, CD45, CD117, and CD163), phagocytosis, and proliferative capacity. Further, thrombopoietin (TPO) significantly stimulated the proliferation of cord blood-derived f-Mphi (CB f-Mphi) at low dosage without inducing a megakaryocytic phenotype. Additional experiments demonstrated that TPO-expanded cord blood-derived f-Mphi (TCB f-Mphi) retained their surface markers and differentiation ability. Treatment with vascular endothelial cell growth factor (VEGF) gave rise to endothelial-like cells, expressing Flt-1, Flk-1, von Willebrand Factor (vWF), CD31, acetylated low density lipoprotein internalization, and the ability to form endothelial-like cell chains. In the presence of lipopolysaccharide (LPS) and 25 mM glucose, the TCB f-Mphi differentiated to express insulin mRNA, C-peptide, and insulin. In vitro functional analysis demonstrated that these insulin-positive cells could release insulin in response to glucose and other secretagogues. These findings demonstrate a potential use of CB f-Mphi and may lead to develop new therapeutic strategy for treating dominant disease.
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PMID:Human umbilical cord blood-derived f-macrophages retain pluripotentiality after thrombopoietin expansion. 1614 25

Besides various gastroduodenal diseases, Helicobacter pylori infection may be involved in autoimmune disorders like rheumatoid arthritis (RA) or idiopathic thrombocytopenic purpura. Such autoimmune disorders are often associated with autoreactive antibodies produced by B-1 cells, a subpopulation of B lymphocytes. These B-1 cells are mainly located in the pleural cavity or mucosal compartment. The existence of H. pylori urease-specific immunoglobulin A (IgA)-producing B cells in the mucosal compartment and of their specific IgM in the sera of acutely infected volunteers suggests the possibility that urease stimulates mucosal innate immune responses. Here, we show for the first time that purified H. pylori urease predominantly stimulates the B-1-cell population rather than B-2 cells, which produce antigen-specific conventional antibodies among splenic B220(+) B cells. The fact that such stimulation of B-1 cells was not affected by the addition of polymyxin B indicates that the effect of purified H. pylori urease was not due to the contamination with bacterial lipopolysaccharide. Furthermore, the production of various B-1-cell-related autoreactive antibodies such as IgM-type rheumatoid factor, anti-single-stranded DNA antibody, and anti-phosphatidyl choline antibody was observed when the splenic B cells were stimulated with purified H. pylori urease in vitro. These findings suggest that H. pylori components, urease in particular, may be among the environmental triggers that initiate various autoimmune diseases via producing autoreactive antibodies through the activation of B-1 cells. The findings shown here offer important new insights into the pathogenesis of autoimmune disorders related to H. pylori infection.
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PMID:Implications for induction of autoimmunity via activation of B-1 cells by Helicobacter pylori urease. 1636 78

Several lines of evidence have suggested that protein tyrosine phosphatases, including CD45 and SHP-1, regulate macrophage activation. Macrophages from mice lacking SHP-1 (motheaten mice) are hyper-responsive to many stimuli, suggesting that SHP-1 may negatively regulate macrophage activation. Herein we report that the repressible/inducible over-expression of wild-type SHP-1 in a subclone of RAW 264.7 macrophages (RAW-TT10 cells) inhibited both TNF secretion and iNOS protein accumulation in response to stimulation with lipopolysaccharide (LPS) and recombinant murine interferon-gamma and led to diminished LPS-mediated tyrosine phosphorylation of vav1. In contrast, expression of a truncated SHP-1 construct previously shown to interfere with endogenous SHP-1 function modestly augmented LPS-mediated TNF and iNOS production and did not inhibit vav1 tyrosine phosphorylation. Taken together, these data provide the first direct evidence that SHP-1 inhibits macrophage activation by LPS and suggest that this effect may be mediated in part by dephosphorylation of vav1.
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PMID:SHP-1 inhibits LPS-mediated TNF and iNOS production in murine macrophages. 1648 32

Strategies of lipopolysaccharide (LPS) stimulation with or without previous toll-like receptor 4 (TLR4) blocking were pursued to investigate the mechanism of LPS-induced preterm delivery in syngeneically impregnated BALB/c and non-obese diabetic (NOD)/LtSz-scid/scid (NOD/SCID [severe combined immunodeficiency] for short) mice. The LPS-stimulated mice were killed at the beginning of preterm labor and pooled placentas were collected in each mouse. Cell surface expression of TLR4, CD80, and intracellular TNF-alpha in placenta CD45(+) cell population was determined by flow cytometry. It displayed that preterm delivery could be induced by LPS in BALB/c, while the NOD/SCID seemed to be resistant to LPS induction. TLR4 expression was not changed in either BALB/c or NOD/SCID mice upon LPS-stimulation, but the CD45(+)CD80(+) cell percentage was elevated in both groups. The CD45(+)TNF-alpha(+) cell percentage was increased merely in BALB/c after the stimulation, while no such trend was observed in NOD/SCID mice. In BALB/c, the effect of LPS on CD80 and TNF-alpha expression could be abrogated by previous TLR4 blocking, subsequently prevent LPS-induced preterm delivery. In another design, NK cell blocking was performed at earlier stage of gestation by injections of anti-asialo GM1 antiserum (ASGM1). It appeared that LPS-induced preterm delivery could be partially prevented by this blocking in BALB/c mice. Such data, together with the diversity of sensitivity to LPS induction observed in BALB/c and NOD/SCID mice, imply that LPS interacts with TLR4, triggers the mobilization of CD45(+)CD80(+) cells, results in elevated production of inflammatory cytokines, and finally results in preterm delivery. In addition, NK cells may be involved in the signaling cascade, and the lack of functional NK cells in the NOD/SCID may be why these mice appeared to be less sensitive to LPS-induced premature labor.
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PMID:Preterm delivery induced by LPS in syngeneically impregnated BALB/c and NOD/SCID mice. 1679 22

The diacylated lipopeptide FSL-1 enhanced the generation of IgG antibodies in TLR2(+/+) mice, but not in TLR2(-/-) mice, when administered together with hen egg lysozyme as an antigen. Escherichia coli lipopolysaccharide enhanced the generation of antigen-specific antibodies in both TLR2(-/-) and TLR2(+/+) mice. In TLR2(+/+) mice, the level of enhancement due to FSL-1 was similar to that caused by lipopolysaccharide. Analysis of the IgG antibodies subclass demonstrated that the level of Th2-type IgG1 antibodies was higher than that of Th1-type IgG2a antibodies. Both FSL-1 and lipopolysaccharide induced production of IL-10 and IL-6 by splenocytes from TLR2(+/+) mice. Lipopolysaccharide also induced production of these cytokines by splenocytes from TLR2(-/-) mice, but FSL-1 did not. Neither FSL-1 nor lipopolysaccharide induced IL-12p70 production by splenocytes from either type of mice. FSL-1 upregulated B7.2 expression in B220(+) cells from TLR2(+/+) mice but not those from TLR2(-/-) mice, whereas lipopolysaccharide upregulated B7.2 expression in B220(+) cells from both types of mice. FSL-1 and, to a lesser extent, lipopolysaccharide activated mitogen-activated protein kinases in splenocytes. FSL-1 and, to a lesser extent, lipopolysaccharide induced the expression of c-Fos, which is known to be involved in Th2-type responses, in splenocytes. Thus, this study demonstrated that FSL-1 possessed TLR2-mediated Th2-type responses in vivo.
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PMID:The diacylated lipopeptide FSL-1 induces TLR2-mediated Th2 responses. 1696 51

Microglial activation is emerging as an important etiologic factor and therapeutic target in neurodegenerative and neuroinflammatory diseases. Techniques have been lacking, however, for measuring the different components of microglial activation independently in vivo. We describe a method for measuring microglial proliferation rates in vivo using heavy water (2H2O) labeling, and its application in screening for drugs that suppress neuro-inflammation. Brain microglia were isolated by flow cytometry as F4/80+, CD11b+, CD45(low) cells, and 2H enrichment in DNA was analyzed by gas chromatography/mass spectrometry. Basal proliferation rate was approximately 1%/week and systemic administration of bacterial lipopolysaccharide (LPS) markedly increased this rate in a dose-dependent manner. Induction of experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice by MOG(35-55) peptide stimulated proliferation of CD45(low) microglia, which could be distinguished from the proliferation of CD45(high) infiltrating monocytes. Minocycline (45 mg/kg/day, i.p.) inhibited resident microglial proliferation in both the LPS and EAE models. Thirteen drugs were then screened for their ability to inhibit LPS-stimulated microglia proliferation. Female C57BL/6 mice were given LPS (1 mg/kg), and concomitant drug treatment while receiving 2H2O label for 7 days. Among the drugs screened, treatment with isotretinoin dose-dependently reduced LPS-induced microglial proliferation, representing an action of retinoids unknown previously. Follow-up studies in the EAE model confirmed that isotretinoin not only inhibited proliferation of microglia but also delayed the onset of clinical symptoms. In conclusion, 2H2O labeling represents a relatively high-throughput, quantitative, and highly reproducible technique for measuring microglial proliferation, and is useful for screening and discovering novel anti-neuroinflammatory drugs.
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PMID:Measurement of brain microglial proliferation rates in vivo in response to neuroinflammatory stimuli: application to drug discovery. 1755 81

The feline immunodeficiency virus (FIV) targets activated CD4-positive helper T cells preferentially, inducing an AIDS-like immunodeficiency in its natural host species, the domestic cat. The primary receptor for FIV is CD134, a member of the tumor necrosis factor receptor superfamily, and all primary viral strains tested to date use CD134 for infection. We examined the expression of CD134 in the cat using a novel anti-feline CD134 monoclonal antibody (MAb), 7D6, and showed that as in rats and humans, CD134 expression is restricted tightly to CD4+, and not CD8+, T cells, consistent with the selective targeting of these cells by FIV. However, FIV is also macrophage tropic, and in chronic infection the viral tropism broadens to include B cells and CD8+ T cells. Using 7D6, we revealed CD134 expression on a B220-positive (B-cell) population and on cultured macrophages but not peripheral blood monocytes. Moreover, macrophage CD134 expression and FIV infection were enhanced by activation in response to bacterial lipopolysaccharide. Consistent with CD134 expression on human and murine T cells, feline CD134 was abundant on mitogen-stimulated CD4+ T cells, with weaker expression on CD8+ T cells, concordant with the expansion of FIV into CD8+ T cells with progression of the infection. The interaction between FIV and CD134 was probed using MAb 7D6 and soluble CD134 ligand (CD134L), revealing strain-specific differences in sensitivity to both 7D6 and CD134L. Infection with isolates such as PPR and B2542 was inhibited well by both 7D6 and CD134L, suggesting a lower affinity of interaction. In contrast, GL8, CPG, and NCSU were relatively refractory to inhibition by both 7D6 and CD134L and, accordingly, may have a higher-affinity interaction with CD134, permitting infection of cells where CD134 levels are limiting.
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PMID:Probing the interaction between feline immunodeficiency virus and CD134 by using the novel monoclonal antibody 7D6 and the CD134 (Ox40) ligand. 1760 74

The complement system normally eliminates bacteria and has a protective effect. However, in an inflammatory setting such as sepsis, an exaggerated or insufficient activation of this cascade can have deleterious effect through the activation of glial cells, secretion of proinflammatory cytokines and generation of other toxic products. The aim of the present study was to investigate the role of the complement cascade in septic encephalopathy, through the passive injection of endotoxin/lipopolysaccharide (LPS) into mice overexpressing the potent complement inhibitor, CR1-related y (Crry-tg). Increased gliosis occurred in brains of endotoxemic mice. Concomitant with this, there was a significant rise in mRNA expression of GFAP, CD45 and proinflammatory molecules, TLR4, TNF-alpha and NO, in these brains. Consistent with the capacity of these inflammatory mediators, there was increased apoptosis as determined by DNA fragmentation and TUNEL staining on LPS treatment, which occurred through the Akt pathway. In addition, there was increased water content in brain, similar to cerebral edema observed in sepsis. Relative to wild-type mice, complement-inhibited mice had an attenuated inflammatory response, decreased edema and reduced apoptosis. Therefore, we demonstrate for the first time that the complement cascade appears to be one of the key players that cause brain pathology in an endotoxemic setting and therefore is a viable therapeutic target.
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PMID:The role of the complement cascade in endotoxin-induced septic encephalopathy. 1792 19

Inflammation has been argued to play a fundamental role in the pathogenesis of Alzheimer's disease. Mice transgenic for mutant human amyloid precursor protein (APP) develop progressive amyloid deposition, gliosis, and cognitive impairment. Paradoxically, intracranial administration of lipopolysaccharide (LPS) to promote neuroinflammation results in a reduction in amyloid-beta peptide (Abeta) burden concurrent with the inflammatory response. To determine whether microglia mediate Abeta clearance after LPS, we used dexamethasone to inhibit the microglial response. Amyloid precursor protein mice were injected intrahippocampally with either LPS or saline and were allowed to survive for 7 days with or without dexamethasone cotreatment. Brain tissue was then analyzed by immunohistochemistry. Hippocampal Abeta burden was reduced 7 days after LPS injection, and this was prevented by cotreatment with dexamethasone. Markers of microglial activation [CD45, complement receptor 3 (CR3), and macrosialin (CD68)] were increased by LPS, and these increases were attenuated by dexamethasone. Dexamethasone failed to block LPS-induced increases in all microglial markers, and Fcgamma receptors II/III and scavenger receptor A were increased by LPS but were unaffected by dexamethasone cotreatment. These results indicate a complex response by microglia to acute LPS treatment, with only some responses sensitive to steroidal anti-inflammatory drug treatment. Nonetheless, microglial activation was necessary to remove Abeta in this model of neuroinflammation.
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PMID:Microglial activation is required for Abeta clearance after intracranial injection of lipopolysaccharide in APP transgenic mice. 1804 Aug 47


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