UNIPROT:P43026 - FACTA Search

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Query: UNIPROT:P43026 (lipopolysaccharide)
62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cholera toxin (CT) is a potent vaccine adjuvant when administered via parenteral, mucosal, or transcutaneous routes. It also inhibits innate inflammatory responses induced by pathogen-derived molecules, such as lipopolysaccharide (LPS). We demonstrated previously that CT promotes the induction of regulatory type 1 T cells (Tr1) as well as T helper type 2 cells (Th2). T cells from mice immunized with antigen in the presence of CT produced high levels of interleukin (IL)-10 and IL-5 and low levels of IL-4 and interferon-gamma (IFN-gamma). Here, we demonstrate that immunization with antigen in the presence of CT induced a population of antigen-specific CD4(+) T cells that produced IL-10 in the absence of IL-4, in addition to cells that coexpressed IL-4 and IL-10 or produced IL-4 only. CT-generated Tr1 cells inhibited antigen-specific proliferation as well as IFN-gamma production by Th1 cells, and this suppression was cell contact-independent. It is interesting that coincubation with Th1 cells significantly enhanced IL-10 production by the Tr1 cells. As IL-10 can promote the differentiation of Tr1 cells, we investigated cytokine production by dendritic cells (DC) following exposure to CT. Previous data showed that CT can modulate the expression of costimulatory molecules and inhibit the production of chemokines and cytokines, including IL-12 and tumor necrosis factor alpha and enhance IL-10 production. Here, we show that CT synergizes with LPS to induce IL-6 and IL-1beta in addition to IL-10 production by immature DC. Therefore, CT may promote the induction of Th2 and Tr1 cells in part via selective modulation of DC cytokine production and costimulatory molecule expression.
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PMID:Effects of cholera toxin on innate and adaptive immunity and its application as an immunomodulatory agent. 1470 72

Adenosine 5'-triphosphate (ATP), which is released from necrotic cells, induces a semimaturation state of dendritic cells (DC), characterized by the up-regulation of costimulatory molecules and the inhibition of proinflammatory cytokines. This action is mediated by cyclic adenosine monophosphate (cAMP) and involves the P2Y11 receptor. As DC express the ecto-enzyme CD39, which converts ATP into adenosine 5'-diphosphate (ADP), the effects of adenine nucleotides diphosphates on molecular signaling [intracellular calcium ([Ca2+]i), cAMP, extracellular signal-regulated kinase 1 (ERK1)], costimulatory molecule expression (CD83), and cytokine production [interleukin (IL)-12, tumor necrosis factor alpha (TNF-alpha), IL-10] were investigated in human monocyte-derived DC. ADP, 2-methylthio-ADP, and ADPbetaS had no effect on cAMP, increased [Ca2+]i, and stimulated the phosphorylation of ERK1. The effect on ERK1 was inhibited by AR-C69931MX, a P2Y12 and P2Y13 antagonist. On the contrary the effect on [Ca2+]i was neither inhibited by AR-C69931MX or by the P2Y1 antagonist MRS-2179. Both effects were inhibited by pertussis toxin. ADPbetaS alone was less potent for up-regulation of CD83 than ATPgammaS and did not increase the CD83 expression by DC stimulated with lipopolysaccharide (LPS). Similar to ATPgammaS, ADPbetaS inhibited the release of IL-12p40, IL-12p70, and TNF-alpha stimulated by LPS (1-100 ng/ml). The inhibitory effect of ADPbetaS on IL-12 release was neither reversed by AR-C69931MX or by MRS-2179. The two nucleotides had opposite effects on IL-10 production: inhibition by ADPbetaS and potentiation by ATPgammaS. In conclusion, ATP can modulate the function of DC, directly via a cAMP increase mediated by the P2Y11 receptor and indirectly via its degradation into ADP, which acts via Gi-coupled receptors coupled to ERK activation and calcium mobilization. These distinct mechanisms converge on the inhibition of inflammatory cytokine production, particularly IL-12, but have a differential effect on IL-10.
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PMID:Involvement of multiple P2Y receptors and signaling pathways in the action of adenine nucleotides diphosphates on human monocyte-derived dendritic cells. 1524 Jul 47

Surfactant protein A (SP-A) is a lung collectin with diverse immunoregulatory activities. SP-A regulates the innate host defense by enhancing phagocytosis of pathogens and modulating the production of nitric oxide and cytokines by immune cells. Additionally, SP-A also modulates the phenotypic and functional properties of the cells of adaptive immune response such as dendritic cells (DCs) and lymphocytes. Bone marrow-derived DCs generated in the presence of SP-A fail to increase lipopolysaccharide-induced upregulation of major histocompatibility complex (MHC) class II and CD86 costimulatory molecule on DCs surface and behaves like "tolerogenic DCs". SP-A may also induce tolerance by suppressing the proliferation of activated T lymphocytes. Thus, based on immunoregulatory properties of SP-A, it may be employed as a therapeutic agent for the treatment of autoimmune disease and organ transplantation.
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PMID:Role of surfactant protein A in the innate host defense and autoimmunity. 1529 82

Chemokines constitute a large family of structurally related proteins that play a role in leukocyte migration and differentiation. Indeed, the early expression of human CXC chemokine receptor 1 (hCXCR1) and hCXCR2 [homologous to mouse interleukin (IL)-8Rbeta] ligands by the epithelium is a hallmark of the mucosal host defense. Mice lack IL-8; however, granulocyte chemotactic protein-2 (GCP-2)/lipopolysaccharide-induced CXC chemokine, a murine homologue of human GCP-2, has 32% and 61% sequence identity to human IL-8 and GCP-2, respectively, and binds hCXCR1, hCXCR2, and mouse IL-8Rbeta. To better understand the role of GCP-2 in adaptive immunity and as a nasal adjuvant, we characterized the exogenous effects of this CXC chemokine on cellular and humoral mucosal immune responses. GCP-2 significantly enhanced serum immunoglobulin G (IgG) and mucosal IgA antibodies through increased cytokine secretion by CD4+ T cells. These alterations in humoral and cellular responses were preceded by an increase in the number of B cells in the nasal tract, a decrease in the number of CD4+ T cells in the nasal tract as well as cervical lymph nodes, and an increase in the number of neutrophils in the nasal tract 12 h after GCP-2 immunization. This chemokine also modulated CD28 expression by CD4+ T cells during CD3epsilon stimulation of wild-type mice. GCP-2 increased CD80 and CD86 expression on B cells during in vitro stimulation in a dose-dependent manner. In contrast, cytokine and costimulatory molecule enhancement by GCP-2 was not induced by lymphocytes from IL-8Rbeta-/- mice, suggesting that GCP-2 modulates cellular immunity in part through IL-8Rbeta interactions.
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PMID:Granulocyte chemotactic protein-2 mediates adaptive immunity in part through IL-8Rbeta interactions. 1535 99

Immature dendritic cells (iDCs) were derived from human peripheral blood monocytes, and treated with 75:25 poly(lactic-co-glycolic acid) (PLGA) microparticles (MPs) or film to assess the resultant dendritic cell (DC) maturation as compared to positive control of lipopolysaccharide (LPS) treatment for DC maturation or negative control of untreated iDCs. The effect of PLGA contact on DC maturation was examined as one possible explanation for the PLGA adjuvant effect we have observed in the enhancement of an immune response to codelivered model antigen, as adjuvants act through the maturation of DCs. Culturing iDCs with PLGA MPs or PLGA film resulted in morphology similar to that of LPS-matured DCs and the association, or possible internalization, of PLGA MPs. Furthermore, biomaterial-treated iDCs demonstrated an increase in MHC class II and costimulatory molecule expression compared to iDCs but to a lower level than that of LPS-matured DCs. Direct iDC contact with PLGA MPs was necessary for maturation. Immature DCs exposed to PLGA MPs were stimulatory of allogeneic T-cell proliferation, whereas cells exposed to PLGA film were not. Further, PLGA MPs supported a moderate delayed type hypersensitivity reaction in mice indicative of in vivo DC maturation. Taken together, these results suggest that PLGA is a DC maturation stimulus and that the form of the biomaterial may influence the extent of DC maturation.
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PMID:Poly(lactic-co-glycolic acid) enhances maturation of human monocyte-derived dendritic cells. 1536 53

Pseudomonas aeruginosa releases a spectrum of well-regulated virulence factors, controlled by intercellular communication (quorum sensing) and mediated through the production of small diffusible quorum-sensing signal molecules (QSSM). We hypothesize that QSSM may in fact serve a dual purpose, also allowing bacterial colonization via their intrinsic immune-modulatory capacity. One class of signal molecule, the N-acylhomoserine lactones, has pleiotropic effects on eukaryotic cells, particularly those involved in host immunity. In the present study, we have determined the comparative effects of two chemically distinct and endobronchially detectable QSSM, N-(3-oxododecanoyl)-L-homoserine lactone (3-oxo-C12-HSL) and 2-heptyl-3-hydroxy-4 (1H)-quinolone or the Pseudomonas quinolone signal (PQS), on human leukocytes exposed to a series of stimuli designed to detect differential immunological activity in vitro. 3-Oxo-C12-HSL and PQS displayed differential effects on the release of interleukin-2 (IL-2) when human T cells were activated via the T-cell receptor and CD28 (a costimulatory molecule). 3-Oxo-C12-HSL inhibited cell proliferation and IL-2 release; PQS inhibited cell proliferation without affecting IL-2 release. Both molecules inhibited cell proliferation and the release of IL-2 following mitogen stimulation. Furthermore, in the presence of Escherichia coli lipopolysaccharide, 3-oxo-C12-HSL inhibited tumor necrosis factor alpha release from human monocytes, as reported previously (K. Tateda et al., Infect. Immun. 64:37-43, 1996), whereas PQS did not inhibit in this assay. These data highlight the presence of two differentially active immune modulatory QSSM from P. aeruginosa, which are detectable endobronchially and may be active at the host/pathogen interface during infection with P. aeruginosa, should the bronchial airway lymphoid tissues prove to be accessible to QSSM.
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PMID:Differential immune modulatory activity of Pseudomonas aeruginosa quorum-sensing signal molecules. 1550 77

After stroke, the blood-brain barrier is transiently disrupted, allowing leukocytes to enter the brain and brain antigens to enter the peripheral circulation. This encounter of normally sequestered brain antigens by the systemic immune system could therefore present an opportunity for an autoimmune response to brain to occur after stroke. In this study, we assessed the immune response to myelin basic protein (MBP) in animals subjected to middle cerebral artery occlusion (MCAO). Some animals received an intraperitoneal injection of lipopolysaccharide (LPS; 1 mg/kg) at reperfusion to stimulate a systemic inflammatory response. At 1 month after MCAO, animals exposed to LPS were more likely to be sensitized to MBP (66.7% versus 22.2%; P=0.007) and had more profound and persistent neurologic deficits than non-LPS-treated animals. Exposure to LPS was associated with increased expression of the costimulatory molecule B7.1 early after stroke onset (P=0.009) and increased brain atrophy 1 month after MCAO (P=0.03). These data suggest that animals subjected to a systemic inflammatory insult at the time of stroke are predisposed to develop an autoimmune response to brain, and that this response is associated with worse outcome. These data may partially explain why patients who become infected after stroke experience increased morbidity.
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PMID:Sensitization to brain antigens after stroke is augmented by lipopolysaccharide. 1593 Nov 60

Various experimental models suggest that the cholesterol-lowering drugs statins may also modulate immune responses. Cellular level studies on human disorders are needed, however, to provide a rational basis for clinical testing of statins as immune therapy. Coeliac disease, a chronic small intestinal inflammation driven by HLA-DQ2 restricted mucosal T cells that are specific for ingested wheat gluten peptides, is in many ways ideal for this purpose. In addition, there is a need for alternative treatment to the gluten-free diet in this disorder. Here we have assessed the effects of atorvastatin on gluten-reactive T cells, dendritic cells and the coeliac mucosa by in vitro culture of biopsies. Atorvastatin inhibited gluten-induced proliferation and specific cytokine production of human intestinal gluten-reactive T cell clones and lines. Dendritic cells exposed to atorvastatin displayed a reduced expression of the costimulatory molecule CD83 upon maturation with lipopolysaccharide. Incubation of intestinal biopsy specimens with atorvastatin in vitro, however, did not influence gluten-induced cytokine release. In conclusion, atorvastatin has specific effects on isolated gluten-reactive T cells and dendritic cells, but does not shut down the gluten-induced production of proinflammatory cytokines in intestinal biopsies.
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PMID:The effects of atorvastatin on gluten-induced intestinal T cell responses in coeliac disease. 1623 21

Costimulation between T cells and antigen-presenting cells is required for adaptive immune responses. CD40, a costimulatory molecule, is expressed in macrophages and microglia. The aberrant expression of CD40 is involved in human diseases including multiple sclerosis, rheumatoid arthritis, and Alzheimer's disease. CD40 expression is induced by a variety of stimuli, including IFN-gamma and lipopolysaccharide (LPS). In this study, we describe the molecular basis by which IFN-beta, a cytokine with immunomodulatory properties, regulates CD40 gene expression. IFN-beta induces CD40 expression in macrophages and microglia at the transcriptional level, and GAS elements in the CD40 promoter are required for IFN-beta-induced CD40 promoter activity. The critical role of signal transducers and activators of transcription-1alpha (STAT-1alpha) in this response was confirmed by utilizing primary microglia from STAT-1alpha deficient mice. IFN-beta induces suppressor of cytokine signaling-1 (SOCS-1) gene expression, which inhibits cytokine signaling by inhibiting activation of STAT proteins. The ectopic expression of SOCS-1 abrogates IFN-beta-mediated STAT-1alpha activation and inhibits IFN-beta-induced CD40 expression. IFN-beta-induced recruitment of STAT-1alpha and RNA Pol II and permissive histone modifications on the CD40 promoter are also inhibited by SOCS-1 overexpression. These novel results indicate that IFN-beta-induced SOCS-1 plays an important role in the negative regulation of IFN-beta-induced CD40 gene expression.
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PMID:IFN-beta-induced SOCS-1 negatively regulates CD40 gene expression in macrophages and microglia. 1657 71

Pentoxifylline (PTX) is a drug used for the treatment of vascular disorders, but it also has a positive therapeutic effect in experimental models of some autoimmune diseases. In this work, we studied the effect of PTX on human monocyte-derived dendritic cells (MDDCs). Immature MDDCs were generated in vitro from monocytes in the presence of recombinant human granulocyte macrophage-colony stimulating factor (rhGM-CSF) and recombinant human interleukin-4 (rhIL-4), while mature MDDCs were obtained by cultivation of immature MDDCs with lipopolysaccharide (LPS). PTX (200 micro g/ml) was added at the beginning of cell cultivation. We found that PTX significantly impaired differentiation and function of immature MDDCs, as judged by the reduced allostimulatory activity of these cells on allogeneic T cells and down-regulation of costimulatory and adhesion molecules, such as CD86, CD40 and CD54. The maturation of MDDCs in the presence of PTX and LPS was characterized by the decreased expression of maturation marker CD83 and costimulatory molecule CD86, as well as lower stimulation of alloreactive T cells compared to the control MDDCs cultivated with LPS alone. PTX-treated MDDCs which were induced to mature with LPS produced lower levels of TNF-alpha, IL-12 and IL-18 and higher levels of IL-10 than corresponding control MDDCs. PTX did not significantly alter endocytosis of dextran by both immature and mature MDDCs. Cumulatively, our results show for the first time that PTX might impair differentiation, maturation and function of human MDDCs in vitro, suggesting an additional mechanism of its immunomodulatory activity.
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PMID:Effect of pentoxifylline on differentiation and maturation of human monocyte-derived dendritic cells in vitro. 1717 83

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