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

The macrophage has previously been implicated in contributing to the renal inflammation associated with hemolytic-uremic syndrome (HUS). However, there is currently no in vivo model detailing the contribution of the renal macrophage to the kidney disease associated with HUS. Therefore, renal macrophage recruitment and inhibition of infiltrating renal macrophages were evaluated in an established HUS mouse model. Macrophage recruitment to the kidney was evident by immunohistochemistry 2 h after administration of purified Stx2 and peaked at 48 h postinjection. Mice administered a combination of Stx2 and lipopolysaccharide (LPS) showed increased macrophage recruitment to the kidney compared to mice treated with Stx2 or LPS alone. Monocyte chemoattractants were induced in the kidney, including monocyte chemoattractant protein 1 (MCP-1/CCL2), macrophage inflammatory protein 1alpha (MIP-1alpha/CCL3), and RANTES (CCL5), in a pattern that was coincident with macrophage infiltration as indicated by immunohistochemistry, protein, and RNA analyses. MCP-1 was the most abundant chemokine, MIP-1alpha was the least abundant, and RANTES levels were intermediate. Mice treated with MCP-1, MIP-1alpha, and RANTES neutralizing antibodies had a significant decrease in Stx2 plus LPS-induced macrophage accumulation in the kidney, indicating that these chemokines are required for macrophage recruitment. Furthermore, mice exposed to these three neutralizing antibodies had decreased fibrin deposition in their kidneys, implying that macrophages contribute to the renal damage associated with HUS.
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PMID:Monocyte chemoattractant protein 1, macrophage inflammatory protein 1 alpha, and RANTES recruit macrophages to the kidney in a mouse model of hemolytic-uremic syndrome. 1722 Mar 20

The role of peripheral dendritic cells (DCs) in hepatitis C virus (HCV) infection is unclear. To determine if persistent infection exerts an inhibitory pressure on HCV-specific innate responses, we analyzed DC function in blood through quantification of cell-associated HCV RNA levels in conjunction with multiparametric flow cytometry analysis of pathogen recognition receptor-induced cytokine expression. Independently of the serum viral load, fluorescence-activated cell sorter-purified total DCs had a wide range of cell-associated HCV genomic RNA copy numbers (mean log(10), 5.0 per 10(6) cells; range, 4.3 to 5.8). Here we report that for viremic patients with high viral loads in their total DCs, the myeloid DC (MDC) subset displayed impaired expression of interleukin-12 (IL-12) and tumor necrosis factor alpha (TNF-alpha) but normal IL-6 or chemokine CCL3 expression in response to poly(I:C) and lipopolysaccharide (LPS). IL-6-expressing cells from this subgroup of viremic patients demonstrated a significant increase (sixfold more) in TNF-alpha(-) IL-12(-) cell frequency compared to healthy donors (mean, 38.8% versus 6.5%; P < 0.0001), indicating a functional defect in a subpopulation of cytokine-producing MDCs ( approximately 6% of MDCs). Attenuation of poly(I:C) and LPS innate sensing was HCV RNA density dependent and did not correlate with viremia or deficits in circulating MDC frequencies in HCV-infected patients. Monocytes from these patients were functionally intact, responding normally on a per-cell basis following stimulation, independent of cell-associated HCV RNA levels. Taken together, these data indicate that detection of HCV genomic RNA in DCs and loss of function in the danger signal responsiveness of a small proportion of DCs in vivo are interrelated rather than independent phenomena.
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PMID:Poly(I:C) and lipopolysaccharide innate sensing functions of circulating human myeloid dendritic cells are affected in vivo in hepatitis C virus-infected patients. 1737 21

The fungal secondary metabolite panepoxydone has been recently described as an inhibitor of NF-kappaB activation which is a pivotal regulator of the inflammatory and immune response. These findings have led to propose that panepoxydone may be useful as anti-inflammatory agent. In this study we investigated for the first time the effects of panepoxydone on inflammatory gene expression in the monocytic cell line MonoMac6, stimulated with lipopolysaccharide (LPS) and the phorbolester 12-O-tetradecanoylphorbol-13-acetate (TPA). DNA microarray analysis of 110 human genes known to be strongly regulated during inflammation, combined with reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) revealed that low micromolar concentrations (12-24 microM) of panepoxydone strongly inhibited the expression of thirty-three NF-kappaB dependent pro-inflammatory genes such as the chemokines CCL3, CCL4, CCL8; CXCL8, CXCL10, CXCL20, the cytokines IL-1, IL-6, TNF-alpha, pro-inflammatory enzymes like COX-2, and components of the REL/NF-kappaB/IkappaB family without significant effects on the expression of house-keeping genes. Panepoxydone strongly inhibited hTNF-alpha, IL-8 and NF-kappaB promoter activity in LPS/TPA stimulated MonoMac6 cells with IC(50) values of 0.5-1 microg/ml by blocking the phosphorylation of IkappaB and subsequent binding of the activated NF-kappaB transcription factor to the DNA. From our data, panepoxydone may serve as lead structure for the development of transcription-based inhibitors of pro-inflammatory gene expression.
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PMID:Influence of the fungal NF-kappaB inhibitor panepoxydone on inflammatory gene expression in MonoMac6 cells. 1738 9

Melatonin possesses a number of important biologic activities including oncostatic, anti-oxidant, and immunostimulatory actions. This study was designed to assess the effects of melatonin on inflammation-related gene expression in lipopolysaccharide (LPS)-stimulated human peripheral blood mononuclear cells (PBMCs), using CombiMatrix 2K Human Inflammation chip. After pretreatment with melatonin (100 microm) for 4 hr, cells were incubated with LPS (1 microg/mL) for 24 hr. We compared gene expression profiles between LPS-treated, melatonin-treated, LSP/melatonin-treated, and control groups. LPS induced the upregulation of 95 genes, compared with controls. Melatonin pretreatment in LPS-stimulated PBMCs suppressed the expression of 23 genes more than twofold. Interestingly, melatonin showed a suppressive effect on the expression of CC chemokine subfamily genes, including CCL2/MCP1, CCL3/MIP1 alpha, CCL4/MIP1 beta, CCL5/RANTES, CCL8/MCP2, CCL20/MDC, and CCL22/MIP3 alpha, in LPS-stimulated PBMCs. This result was confirmed by reverse transcriptase polymerase chain reaction. Among the CC chemokine subfamily genes, particularly, the expression of CCL2 and CCL5 was markedly downregulated by melatonin in LPS-stimulated PBMCs. The secretion levels of CCL2 and CCL5 were measured using enzyme-linked immunosorbent assay. Stimulation of PBMCs by LPS induced the secretion of CCL2 (2334.3 +/- 161.4 pg/mL, mean +/- S.E.M.), whereas melatonin pretreatment (153.0 +/- 3.8 pg/mL) inhibited the LPS-induced secretion of CCL2. Melatonin pretreatment (2696.2 +/- 385.3 pg/mL) also inhibited the LPS-induced secretion of CCL5 (4679.6 +/- 107.5 pg/mL). Taken together, these results suggest that melatonin may have a suppressive effect on LPS-induced expression of CC chemokine genes, especially CCL2 and CCL5, which may explain its beneficial effects in the treatment of various inflammatory conditions.
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PMID:Melatonin inhibits lipopolysaccharide-induced CC chemokine subfamily gene expression in human peripheral blood mononuclear cells in a microarray analysis. 1764 90

NF-kappaB is a key mediator of inflammation. Here, we mapped the genome-wide loci bound by the RELA subunit of NF-kappaB in lipopolysaccharide (LPS)-stimulated human monocytic cells, and together with global gene expression profiling, found an overrepresentation of the E2F1-binding motif among RELA-bound loci associated with NF-kappaB target genes. Knockdown of endogenous E2F1 impaired the LPS inducibility of the proinflammatory cytokines CCL3(MIP-1alpha), IL23A(p19), TNF-alpha, and IL1-beta. Upon LPS stimulation, E2F1 is rapidly recruited to the promoters of these genes along with p50/RELA heterodimer via a mechanism that is dependent on NF-kappaB activation. Together with the observation that E2F1 physically interacts with p50/RELA in LPS-stimulated cells, our findings suggest that NF-kappaB recruits E2F1 to fully activate the transcription of NF-kappaB target genes. Global gene expression profiling subsequently revealed a spectrum of NF-kappaB target genes that are positively regulated by E2F1, further demonstrating the critical role of E2F1 in the Toll-like receptor 4 pathway.
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PMID:Genome-wide mapping of RELA(p65) binding identifies E2F1 as a transcriptional activator recruited by NF-kappaB upon TLR4 activation. 1770 33

Macrophages are key effectors in demyelinating diseases of the central and peripheral nervous system by phagocytosing myelin and releasing immunoregulatory mediators. Here, we report on a distinct, a priori anti-inflammatory reaction of macrophages phagocytosing myelin upon contact with damaged nerve tissue. Macrophages rapidly invaded peripheral (sciatic) and central (optic) nerve tissues in vitro, readily incorporated myelin and expressed high levels of phagocytosis-associated molecules (e.g., Fc and scavenger receptors). In contrast, factors involved in antigen presentation (MHC class-II, CD80, CD86) revealed only a restricted expression. In parallel, a highly ordered appearance of cytokines and chemokines was detected. IL-10, IL-6, CCL22, and CXCL1 were immediately but transiently induced, whereas CCL2, CCL11, and TGFbeta revealed more persisting levels. Such a profile would attract neutrophils, monocytes/macrophages, and Th2 cells as well as bias for a Th2-supporting environment. Importantly, proinflammatory/Th1-supporting factors, such as TNFalpha, IL-12p70, CCL3, and CCL5, were not induced. Still the simultaneous presence of TGFbeta and IL-6 could assist Th17 development, further depending on yet not present IL-23. The release pattern was clearly distinct from reactive phenotypes induced in isolated macrophages and microglia upon treatment with IL-4, IL-13, bacterial lipopolysaccharide, IFNgamma, or purified myelin. Nerve-exposed macrophages thus commit to a unique functional orientation.
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PMID:Myelin-phagocytosing macrophages in isolated sciatic and optic nerves reveal a unique reactive phenotype. 1806 69

ADP-ribosylation factor 6 (ARF6) is a widely expressed GTPase that influences both membrane traffic and actin cytoskeleton function. Its role in dendritic cells (DC) has not previously been investigated. We analysed the effect of retroviral expression of ARF6 GDP/GTP binding and other functional mutants in primary murine DC. Maturation in response to lipopolysaccharide (LPS) proceeded normally in DC expressing ARF6 mutants and production of inflammatory cytokines was similarly unaffected. Although LPS-stimulated macropinocytosis was suppressed by expression of the GTP-binding Q67L ARF6 mutant we detected no overall activation of ARF6 by LPS. The ability of immature DC to migrate towards CCL3 and to a lesser extent, of mature DC to migrate towards CCL19, was compromised by expression of either the Q67L or the GDP-binding T44N mutant. Examination of the actin cytoskeleton in these cells revealed that both mutants strongly inhibited the formation of F-actin-rich podosomes, providing a possible explanation for the effects of ARF6 mutants on DC migration. Thus, these studies identify responses in DC that require normal ARF6 function, though not necessarily further ARF6 activation. They reveal for the first time a role for ARF6 in podosome formation and demonstrate functional effects of the T44N ARF6 mutant.
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PMID:A role for ARF6 in dendritic cell podosome formation and migration. 1828 66

Apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3G (APOBEC3G) has recently been identified as a potent antiviral protein. Here, we examined the expression and regulation of APOBEC3G in human brain tissues and the cells of central nervous system (CNS). Similar to the immune cells, human brain tissue and the CNS cells expressed APOBEC3G at both mRNA and protein levels. The expression of APOBEC3G could be up-regulated in human neuronal cells (NT2-N) and astrocytes (U87-MG) by interferons (IFN-alpha, beta and gamma), interleukin-1 (IL-1), and tumor necrosis factor. Other cytokines (IL-4, IL-6 and transforming growth factor beta1) and CC-chemokines (CCL3, 4 and 5), however, had little impact on the expression of APOBEC3G. In addition, pseudotyped HIV-1 infection and cytokine/chemokine-enriched supernatants from lipopolysaccharide-stimulated macrophage cultures induced APOBEC3G expression in NT2-N cells. APOBEC3G expressed in the neuronal cells and astrocytes was biologically functional, as the suppression of APOBEC3G expression by the specific siRNA led to increase of pseudotyped HIV-1 replication in these cells. These findings provide direct and compelling evidence that there is intracellular expression and regulation of functional APOBEC3G in the neuronal cells, which may be one of innate defense mechanisms involved in the neuronal protection in the CNS.
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PMID:Expression and regulation of antiviral protein APOBEC3G in human neuronal cells. 1902 80

The aim of this study was to clarify the effect of bestatin, an aminopeptidase inhibitor, on the production of cytokines from peripheral blood monocytes and alveolar macrophages (AM). Human monocytes isolated from peripheral blood of healthy volunteers were incubated with or without lipopolysaccharide (LPS) in the presence or absence of bestatin. AM obtained from patients with sarcoidosis were incubated in the presence or absence of bestatin. The concentration of cytokines in the culture supernatant was determined by enzyme-linked immunosorbent assay. The expression of mRNA was determined by reverse transcription polymerase chain reaction. Bestatin suppressed the production and expression of proinflammatory cytokines and chemokines, interleukin (IL)-6, CXCL8/IL-8, CCL3/macrophage inflammatory protein (MIP)-1alpha by LPS-stimulated monocytes. The mean percentage of the inhibition of IL-6, CXCL8/IL-8, CCL3/MIP-1alpha by bestatin at a concentration of 50 microg/mL was 71.2%, 29.7% and 61.0%, respectively. On the other hand, bestatin increased the production and mRNA expression of IL-10 by LPS-stimulated monocytes. The treatment with bestatin significantly inhibited the production of IL-6 and CXCL8/IL-8 by AM from patients with sarcoidosis. The data presented here indicate that bestatin suppresses the production of the pro-inflammatory cytokines and stimulates the anti-inflammatory cytokine by activated human monocytes. This study suggests that bestatin may be useful as an anti-inflammatory agent in various inflammatory diseases.
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PMID:Bestatin, an inhibitor for aminopeptidases, modulates the production of cytokines and chemokines by activated monocytes and macrophages. 1903 3

The parapoxvirus orf virus causes pustular dermatitis in sheep and is transmissible to humans. The virus encodes a secreted chemokine-binding protein (CBP). We examined the ability of this protein to inhibit migration of murine monocytes in response to CC inflammatory chemokines, using chemotaxis assays, and its effects on monocyte recruitment into the skin, using a mouse model in which inflammation was induced with bacterial lipopolysaccharide. CBP was shown to bind murine chemokines CCL2, CCL3 and CCL5 with high affinity by surface plasmon resonance and it completely inhibited chemokine-induced migration of monocytes at a CBP:chemokine molar ratio of 4:1. In the mouse, low levels of CBP potently inhibited the recruitment of Gr-1+/CD11b+ monocytes to the site of inflammation in the skin but had little effect on neutrophil recruitment, suggesting that this factor plays a role in disrupting chemokine-induced recruitment of specific immune cell types to infection sites.
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PMID:Orf virus-encoded chemokine-binding protein is a potent inhibitor of inflammatory monocyte recruitment in a mouse skin model. 1926 45


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