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)

Monophosphoryl lipid A (MPL) is a nontoxic derivative of lipopolysaccharide (LPS) that exhibits adjuvant properties similar to those of the parent LPS molecule. However, the mechanism by which MPL initiates its immunostimulatory properties remains unclear. Due to the involvement of Toll-like receptors in recognizing and transducing intracellular signals in response to LPS, the aim of the present study was to determine the ability of MPL to utilize the Toll-like receptor 2 (TLR2) and TLR4. We provide evidence that MPL differentially utilizes TLR2 and TLR4 for the induction of tumor necrosis factor alpha, interleukin 10 (IL-10), and IL-12 by purified human monocytes as well as by human peripheral blood mononuclear cells. Assessment of NF-kappa B activity demonstrated that MPL utilized TLR2 and especially TLR4 for the activation of NF-kappa B p65 by human monocytes. In addition, stimulation of human monocytes by MPL led to an up-regulation of the costimulatory molecules CD80 and CD86, an effect that could be reduced by pretreatment of cells with a monoclonal antibody to TLR2 or TLR4. Analysis of MPL-induced activation of the extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein (MAP) kinases revealed that MPL utilized both TLR2 and TLR4 for the phosphorylation of ERK1/2, while TLR4 was the predominant receptor involved in the ability of MPL to phosphorylate p38. Moreover, using selective inhibitors for MAP kinase kinase (PD98059) and p38 (SB203580), we show that ERK1/2 exhibited differential effects on production of TNF-alpha and IL-12 p40 by human monocytes, whereas MPL-induced activation of p38 appeared to be predominantly involved in production of IL-10 and IL-12 p40 by MPL-stimulated monocytes. Taken together, these findings aid in understanding the cellular mechanisms by which MPL induces host cell activation and subsequent adjuvant properties.
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PMID:Role of innate immune factors in the adjuvant activity of monophosphoryl lipid A. 1270 21

Since dendritic cells (DCs) play a critical role in establishing antigen-specific adaptive immune responses, in the past several years, therapeutic strategies using genetically modified DCs against cancer and infectious diseases have attracted increasing attention. In the present study, we demonstrated that RGD fiber-mutant adenovirus vector (AdRGD) exhibited markedly superior gene transduction efficiency in mouse bone marrow-derived DCs (mBM-DCs) compared to conventional adenovirus vector (Ad). Likewise, this vector exhibited superior major histocompatibility complex class I-restricted presentation of antigen derived from the delivered gene in mBM-DCs. In order to investigate the effect of Ad-infection on the DC-differentiation process (maturation), we used three types of AdRGD and three conventional Ad to transduce mBM-DCs. These vectors carried either no transgene, LacZ gene, or gp100 gene. Infection by any of the Ad vectors enhanced the expression of MHC class II molecules in mBM-DCs. CD80, CD86, and CD40 expression and IL-12 production were more efficient in AdRGD-infected mBM-DCs than in conventional Ad-infected cells. Contrary to our expectations, endocytotic activity of mBM-DCs decreased only slightly upon Ad-infection, whereas antigen uptake by lipopolysaccharide (LPS)-driven mature mBM-DCs was significantly impaired. However, our reverse transcription-polymerase chain reaction analysis revealed that Ad-infection resulted in the upregulation of the chemokine receptor CCR7 and downregulation of CCR6 in mBM-DCs and LPS-stimulated cells. We, therefore, concluded that Ad-infection directly influenced DC-maturation, although the effects were milder than under LPS-stimulation. In addition, this change in the immunologic properties of DCs resulted primarily from an increase in the number of Ad-particles capable of invading the cells rather than from the expression of foreign genes. AdRGD-infection caused greater induction of maturation than conventional Ad-infection, irrespective of the type of transgene inserted.
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PMID:Gene transduction efficiency and maturation status in mouse bone marrow-derived dendritic cells infected with conventional or RGD fiber-mutant adenovirus vectors. 1271 12

Dendritic cells (DC) modulate immune responses depending on the nature of the antigens. Receptors capable of discriminating these antigens on the basis of the pathogen-associated molecular patterns (PAMP) belong to the Toll-like receptor (TLR) family. The macrophage-activating lipopeptide 2 kDa (MALP-2), a synthetic lipopeptide derived from Mycoplasma fermentans, signals through TLR-2 and TLR-6. The aim of this study was to examine whether MALP-2 can modulate the functional properties of human monocyte-derived DC. The effects of this treatment were compared to those of the TLR-4 agonist lipopolysaccharide (LPS). To ensure clinical applicability, DC were generated under serum-free conditions. MALP-2 and LPS stimulation induced the expression of CD83 and increased the expressions of CD80, CD86, HLA-ABC and CD40. Furthermore, both substances decreased the endocytotic capacity of DC and induced the release of bioactive TNF-alpha and IL-10, whereas LPS additionally increased IL-12 release. Pretreatment with both substances boosted the allostimulatory capacity of DC. In a coculture with autologous lymphocytes, either MALP-2 or LPS pretreated DC induced a marked proliferation of lymphocytes, but only DC prestimulated with MALP-2 activated lymphocytes to produce the cytokines IL-4, IL-5 and IFN-gamma. No polarisation of lymphocytes into T-helper (Th)1 or Th2 was detected. These data indicate that MALP-2 is a potential candidate to modulate DC for clinical applications.
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PMID:Synthetic mycoplasma-derived lipopeptide MALP-2 induces maturation and function of dendritic cells. 1277 64

In this study we investigated whether berberine-mediated induction of interleukin-12 (IL-12) production in antigen-presenting cells could regulate a cytokine profile of antigen-primed CD4+ T helper (Th) cells. Pretreatment with berberine induced IL-12 production in both macrophages and dendritic cells, and significantly increased the levels of IL-12 production in lipopolysaccharide-stimulated macrophages and in CD40 ligand-stimulated dendritic cells. Importantly, berberine pretreatment of macrophages increased their ability to induce interferon-gamma (IFN-gamma) and reduced their ability to induce IL-4 in antigen-primed CD4+ T cells. Berberine did not influence the macrophage cell surface expression of the class II major histocompatibility complex molecule, the co-stimulatory molecules CD80 and CD86, and intracellular adhesion molecule-1. Addition of neutralizing anti-IL-12p40 monoclonal antibody to cultures of berberine-pretreated macrophages and CD4+ T cells restored IL-4 production in antigen-primed CD4+ T cells. The in vivo administration of berberine resulted in the enhanced induction of IL-12 production by macrophages when stimulated in vitro with lipopolysaccharide or heat-killed Listeria monocytogenes, leading to the inhibition of the Th type 2 cytokine profile (decreased IL-4 and increased IFN-gamma production) in antigen-primed CD4+ T cells. These findings may point to a possible therapeutic use of berberine or medicinal plants containing berberine in the Th type 2 cell-mediated immune diseases such as allergic diseases.
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PMID:Induction of interleukin-12 production in mouse macrophages by berberine, a benzodioxoloquinolizine alkaloid, deviates CD4+ T cells from a Th2 to a Th1 response. 1280 87

Murine Kupffer cells (KCs) are heterogeneous and survive only for a short time in vitro. Here, a clonal, murine KC line was generated from transgenic mice, expressing the thermolabile mutant tsA58 of the Simian virus 40 large T antigen under the control of the H-2K(b) promoter. Thirty-three degrees Celsius and 37 degrees C but not 39 degrees C have been permissive for growth of the clone; it required conditioned media from hepatocytes and endothelial cells for proliferation. In contrast to primary cells, the cells of the clone were uniform, survived detachment, and could therefore be analyzed by cytofluorimetry. The clone, as primary KCs, constitutively expressed nonspecific esterase, peroxidase, MOMA-2, BM8, scavenger receptor A, CD14, and Toll-like receptor 4 (TLR4); the antigen-presenting molecules CD40, CD80, and CD1d; and endocytosed dextran-fluorescein isothiocyanate. It lacked complement, Fc receptors, F4/80 marker, and the phagosomal coat protein tryptophan aspartate-containing coat protein (TACO). The clone exhibited CD14- and TLR4/MD2-independent, plasma-dependent lipopolysaccharide (LPS) binding, Escherichia coli and Streptococcus pneumoniae phagocytosis, and LPS- and interferon-gamma-induced NO production but no tumor necrosis factor alpha, interleukin (IL)-6, or IL-10 release. The large size, surface-marker expression, and capacity to clear gram-negative and -positive bacteria indicate that the clone was derived from the periportal, large KC subpopulation. The clone allows molecular studies of anti-infective and immune functions of KCs.
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PMID:Generation and functional characterization of a clonal murine periportal Kupffer cell line from H-2Kb -tsA58 mice. 1283 42

Although antigen-loaded dendritic cells (DC) are being investigated as antitumor vaccines, which DC differentiation state is most effective is not clear. Three DC functions that may be critical for immunization potential are expression of CD80/86, cytokine production following CD40 engagement, and migration to chemokine receptor 7-binding chemokines. We therefore examined highly purified human monocyte-derived immature and mature DC for these properties from normal donors and cancer patients. Although high expression of CD80/86 and migration to 6Ckine + macrophage-inflammatory protein-3beta were properties of mature DC, cytokine production following CD40 ligation was superior by immature DC. Loss of cytokine secretion occurred with multiple maturation conditions, was not apparently reversible, and was also seen with lipopolysaccharide stimulation in correlation with down-regulated Toll-like receptor expression. Our results suggest that the functions thought to contribute to optimal T cell priming are not coexpressed by the same DC population and that immature and mature DC likely possess distinct CD40-mediated signaling events.
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PMID:Disparate functions of immature and mature human myeloid dendritic cells: implications for dendritic cell-based vaccines. 1283 44

Platelet factor 4 (PF4) is a CXC chemokine secreted by activated platelets. PF4 has been shown to promote monocyte survival and induce the differentiation of monocytes into macrophages. However, the effect of PF4 on differentiation of monocytes into dendritic cells (DC) has yet to be determined. As reported previously, monocytes cultured in RPMI medium containing FCS, granulocyte macrophage colony stimulating factor and IL-4 differentiated into CD1a+ DC. When PF4 was added, the expression of CD1a on DC was inhibited. This inhibitory effect was not observed with the other platelet-derived CXC chemokine, beta-thromboglobulin. The relative number of CD1a- DC increased from 17 to 92% when the PF4 concentration was increased from 0 to 10 micro g/ml. The inhibitory effect of PF4 on CD1a expression was reversed by 50 U/ml heparin. DC developed in the PF4-containing media appeared more adhesive to plastic culture wells and had higher light side scatter by flow cytometry. Immunophenotypically, monocyte-derived DC in the presence of increasing concentrations of PF4 proportionally expressed higher CD86 and lower HLA-DR. The levels of CD11c, CD40 and CD80 remained unchanged with or without PF4. Both CD1a+ DC and CD1a- DC were negative for CD14, CD68 and CD83. Functionally, DC developed in the presence of PF4 had their secretion of tumor necrosis factor-alpha and IL-12 reduced by 75 +/- 10 and 79 +/- 13% respectively when they were stimulated by 100 ng/ml lipopolysaccharide and 50 ng/ml IFN-gamma. CD1a- DC developed in the presence of PF4 were not as active as the control CD1a+ DC in stimulating allogeneic T cells to proliferate. In addition, CD1a- DC were less potent in priming naive CD4+ T cells to secrete both type 1 and 2 cytokines. These results indicate that PF4 can influence differentiation and function of monocyte-derived DC.
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PMID:Effect of CXC chemokine platelet factor 4 on differentiation and function of monocyte-derived dendritic cells. 1288 38

Monocytes/macrophages in ischemic tissues are involved in inflammation and suppression of adaptive immunity via secretion of proinflammatory cytokines and reduced ability to trigger T cells, respectively. We subjected human mononuclear cells and mouse macrophages to hypoxia and reoxygenation, the main constituents of ischemia and reperfusion, and added lipopolysaccharide (LPS) to simulate bacterial translocation, which frequently accompanies ischemia. We monitored the secretion of tumor necrosis factor alpha (TNF-alpha) and the surface expression of human leukocyte antigen-DR and the costimulatory molecules CD80 and CD86 on monocytes/macrophages. Hypoxia selectively reduced the surface expression of CD80 (P<0.01), and synergistically with LPS, it enhanced TNF-alpha secretion (P<0.003). Reoxygenation reversed both phenomena. In the mouse macrophage cell line RAW 264.7, hypoxia reduced the surface expression of CD80 and increased its concentrations in the supernatants (P<0.01). Down-regulation of the mRNA coding for the membrane-anchored CD80 was observed, suggesting that hypoxia triggers alternative splicing to generate soluble CD80. Cumulatively, these results suggest that hypoxia simultaneously affects monocytes/macrophages to enhance inflammation and reduce their ability to initiate adaptive-immunity responses associated with ischemic injury.
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PMID:Hypoxia reduces CD80 expression on monocytes but enhances their LPS-stimulated TNF-alpha secretion. 1288 36

The effect of targeting strategies for improving the interaction of liposomal PorA with dendritic cells (DC) on the immunogenicity of PorA was investigated. PorA, a major antigen of Neisseria meningitidis, was purified and reconstituted in different types of (targeted) liposomes, i.e., by using mannose or phosphatidylserine as targeting moieties, or with positively charged liposomes. We studied the efficiency of liposome uptake and its effect on the maturation of and interleukin 12 (IL-12) production by murine DC. Moreover, mice were immunized subcutaneously to study the localization and immunogenicity of PorA liposomes. Uptake of liposomes by DC was significantly increased for targeted liposomes and resulted in the maturation of DC, but to various degrees. Maturation markers (i.e., CD80, CD86, major histocompatibility complex class II, and CD40) showed enhanced expression on DC incubated with targeted PorA liposomes relative to those incubated with nontargeted PorA liposomes. Moreover, only the uptake of targeted PorA liposomes induced production of IL-12 by DC, with levels similar to those produced by lipopolysaccharide (LPS)-pulsed DC. Mannose-targeted PorA liposomes administered subcutaneously had an increased localization in draining lymph nodes compared to nontargeted PorA liposomes. Liposomes in draining lymph nodes interacted preferentially with antigen-presenting cells, an effect that was enhanced with targeted PorA liposomes. Immunization studies showed an improvement of the bactericidal antibody response (i.e., increased number of responders) generated by targeted PorA liposomes compared to that generated by nontargeted ones or LPS-containing outer membrane vesicles. In conclusion, the use of targeted PorA liposomes results in an improved uptake by and activation of DC and an increased localization in draining lymph nodes. These effects correlate with an enhanced immune response toward the vaccine.
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PMID:Liposomal meningococcal B vaccination: role of dendritic cell targeting in the development of a protective immune response. 1293 66

We have studied the effect of mycophenolate mofetil (MMF), a new drug used in prevention of transplant rejection, on differentiation, maturation and allostimulatory activity of human monocyte-derived dendritic cells (MDDC). MDDC were generated in vitro with granulocyte macrophage-colony stimulating factor (GM-CSF) and interleukin (IL)-4 in the presence or absence of MMF. MMF reduced the number of immature MDDC in culture, dose-dependently, by inducing apoptosis and inhibited their stimulatory activity on allogeneic lymphocytes. These changes correlated with down-regulation of co-stimulatory and adhesion molecules such as CD40, CD54, CD80 and CD86. No differences were observed in mannose receptor (MR)-mediated endocytosis, measured by the uptake of fluorescein isothiocyanate (FITC)-dextran. MDDC differentiated in the presence of MMF showed significantly reduced maturation upon stimulation with lipopolysaccharide, as judged by lower expresson of CD83 and co-stimulatory molecules, lower production of tumour necrosis factor (TNF)-alpha, IL-10, IL-12 and IL-18 as well as lower stimulation of alloreactive T cells including naive CD4+ CD45RA+ T cells. In contrast, MDDC matured in the presence of MMF showed a more marked decrease in the FITC-dextran uptake than mature MDDC cultivated without MMF and the phenomenon correlated with down-regulation of the MR expression. These results suggest that MMF impairs differentiation, maturation and function of human MDDC in vitro, which is an additional mechanism of its immunosuppressive effect.
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PMID:Mycophenolate mofetil inhibits differentiation, maturation and allostimulatory function of human monocyte-derived dendritic cells. 1297 56


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