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)

Astrocytes and microglia from cerebral cortex of 3-, 6-, 12-, and 24-month-old F344 male rat donors showed progressively greater proliferation during primary culture. Microglia from aging donor brains exhibited an amoeboid-like morphology and express antigens characteristic of an activated state (e.g., major histocompatibility complex class II). Moreover, microglia from aging donors were less sensitive to several types of regulators. Granulocyte-macrophage colony stimulating factor stimulated proliferation in microglia from young, but not aging brains. Transforming growth factor (TGF)-beta1 inhibited astrocytic and microglial proliferation in cultures from young, but not aging donors. Similarly, the inhibition of lipopolysaccharide-induced NO production by TGF-beta1 in microglia was impaired in cultures from 12-month (middle-age) brains. Another aging change detected by middle age, increased glial fibrillary acidic protein (GFAP) expression, also persisted in astrocytes from 12- to 24-month-old brains, as evaluated by increased activity of a 5'-upstream GFAP promoter construct. Thus, both microglia and astrocytes originated from aging cerebral cortex maintain in vitro at least some of the activated phenotypes of aging glia that are observed in vivo. This new in vitro cell model may allow efficient analysis of glial age changes.
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PMID:Age-related activation of microglia and astrocytes: in vitro studies show persistent phenotypes of aging, increased proliferation, and resistance to down-regulation. 956 10

The attenuated S. typhimurium SL3261 (aroA) strain causes mild infections in BALB/c mice. We were able to exacerbate the disease by administering anti-interleukin-12 (IL-12) antibodies, resulting in bacterial counts in the spleens and livers of anti-IL-12-treated mice that were 10- to 100-fold higher than the ones normally observed in premortem mice; yet the animals showed only mild signs of illness. Nevertheless, they eventually died of a slow, progressive disease. Mice infected with salmonellae become hypersusceptible to endotoxin. We found that IL-12 neutralization prevented the death of infected mice following subcutaneous injection of lipopolysaccharide. Granulomatous lesions developed in the spleens and livers of control animals, as opposed to a widespread infiltration of mononuclear cells seen in the organs of anti-IL-12-treated mice. In the latter (heavily infected), salmonellae were seen within mononuclear cells, indicating an impairment of the bactericidal or bacteriostatic ability of the phagocytes in the absence of biologically active IL-12. Gamma interferon (IFN-gamma) levels were reduced in the sera and tissue homogenates from anti-IL-12-treated mice compared to those in control animals. Furthermore, fluorescence-activated cell sorter analysis on spleen cells showed that IL-12 neutralization impaired the upregulation of I-Ad/I-Ed antigens on macrophages from infected mice. Inducible nitric oxide synthase and IFN-gamma mRNA production was down-regulated in anti-IL-12-treated mice, which also showed an increased production of IL-10 mRNA and a decrease in nitric oxide synthase activity in the tissues. Administration of recombinant IFN-gamma to anti-IL-12-treated mice was able to restore host resistance, granuloma formation, and expression of major histocompatibility complex class II antigens in F4/80(+) and CD11b+ spleen cells.
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PMID:Interleukin-12 is required for control of the growth of attenuated aromatic-compound-dependent salmonellae in BALB/c mice: role of gamma interferon and macrophage activation. 974 77

The lipopolysaccharide (LPS) structure of Salmonella typhimurium has been correlated with the virulence of wild-type strain LT2. Mutants of LT2 with truncated polysaccharide portions of LPS are less virulent than strains with a complete LPS structure. Polyclonal T cells and monoclonal T-cell hybridomas were more reactive to heat-killed rough mutants than to heat-killed smooth strains, as measured by interleukin-2 (IL-2) production. Using a large panel of strains with truncated LPS molecules, we found that T-cell reactivity decreased with certain lengths of polysaccharide. The decreased response was not due to differential phagocytic uptake, IL-12 production, or major histocompatibility complex class II surface expression by macrophages. Also, LT2 did not mediate any global suppression since addition of LT2 did not diminish the response of T cells specific for antigens unrelated to Salmonella. In an experiment in which processing times were varied, we found that antigens from rough strains were processed and presented more quickly than those associated with smooth strains. At longer processing times, epitopes from LT2 were presented well. We hypothesize that the slower antigen processing and presentation of wild-type Salmonella may be caused by masking of surface antigens by the longer polysaccharide portion of smooth LPS. This blocking of effective antigen presentation may contribute to the virulence of Salmonella.
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PMID:The polysaccharide portion of lipopolysaccharide regulates antigen-specific T-cell activation via effects on macrophage-mediated antigen processing. 986 32

Brain prostanoid levels are normally low but can increase after ischemia and during inflammatory and infectious diseases. High prostanoid levels can affect brain function in several ways. In particular, prostaglandin E2 (PGE2) might exert both immunodepressive and proinflammatory actions. The present short review focuses on the regulation of prostanoid synthesis in microglial cultures and on the possible role of PGE2 in the down-regulation of microglial activation induced by lipopolysaccharide (LPS). Our studies were carried out using purified mouse or rat microglial cultures. LPS induced a dose-dependent expression of the inducible isoform of cyclooxygenase (COX-2), both in neonatal and adult microglial cultures. In the latter, the inducibility of COX-2 increased with time in culture, paralleling the acquisition of a more 'activated' microglial phenotype, and appeared to account for the time-dependent increase in the PGE2/TXB2 production ratio. The LPS-induced COX-2 expression and prostanoid production were down-regulated by potentially neurotoxic agents, such as nitric oxide (NO), the proinflammatory cytokine IFN-gamma (which acted both directly and indirectly, through its NO-inducing activity) and the HIV regulatory protein tat. On the other hand, COX-2 expression was up-regulated by the macrophage-deactivating cytokine TGF-beta 1, by exogenous PGE2 itself, which acted through EP2 receptors linked to cyclic AMP generation, and by non steroidal anti-inflammatory drugs. Interestingly, PGE2 utilized the same EP2 receptor-mediated signal transduction mechanism to down-regulate the expression of the inducible NO synthase and the production of NO. Largely, but not exclusively, through its effect on cyclic AMP, PGE2 can also: i) depress the expression of major histocompatibility complex class II antigens and of the costimulatory molecule B7-2; ii) down-regulate TNF and up-regulate IL-10 microglial production; iii) inhibit microglial IL-12 secretion. These observations, together with literature data on in vivo models of central nervous system (CNS) diseases, suggest a neuroprotective role of PGE2 in pathological conditions.
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PMID:Regulation of prostanoid synthesis in microglial cells and effects of prostaglandin E2 on microglial functions. 989 49

The induction of an immune response or tolerance is mediated by corresponding subsets of dendritic cells (DC). However, the property of tolerogenic DC is not clear. Recently, we have characterized a population of CD11c+ splenic DC derived from long-term mixed leucocyte culture (LT-MLC), which are able to proliferate upon stimulation and have a strong primary mixed leucocyte reaction (MLR)-stimulating activity in conventional MLR. In this study, we show that, in contrast to the irradiated ones, non-irradiated LT-MLC-derived DC induce polyclonal antigen-specific T-cell hyporesponsiveness when cocultured with allogeneic splenocytes for 3-11 days. The degree of the hyporesponsiveness increased with the length of coculture. Although these DC expressed major histocompatibility complex class II and B7 costimulatory molecules, which are down-regulated during coculture, they expressed very low or undetectable CD40 before and after coculture, respectively. The CD40-deficient DC spontaneously produce interleukin-10 (IL-10), but not IL-12. The skewed balance between IL-10 and IL-12 is associated with their capability to induce T-cell hyporesponsiveness, because a neutralizing antibody to IL-10, exogenous recombinant IL-12 or lipopolysaccharide (LPS) significantly blocked the hyporesponsiveness. Accordingly, infusion of a small number of non-irradiated LT-MLC-derived DC (5x105) significantly prolonged the survival of a vascularized heterotopic murine heart transplant, whereas irradiated DC accelerated graft rejection. These data suggest that CD40-deficient DC producing IL-10, but not IL-12 can induce T-cell hyporesponsiveness in vitro and in vivo.
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PMID:CD40-deficient dendritic cells producing interleukin-10, but not interleukin-12, induce T-cell hyporesponsiveness in vitro and prevent acute allograft rejection. 1054 Feb 14

Mature B lymphocytes respond to antigen receptor ligation by phenotypic changes, including up-regulation of major histocompatibility complex class II molecules and expression of B7.2, which are required for initiating and sustaining a productive interaction with T helper cells. We have previously demonstrated that neonatal B cells fail to show a similar up-regulation of class II and B7.2 expression following B-cell receptor (BCR) ligation, although these responses could be induced by other stimuli. Here we demonstrate that immature B cells from adult bone marrow exhibit even more profound defects in these responses, as they fail to up-regulate class II in response to either BCR ligation or interleukin-4. Moreover, bone marrow-derived, immature B cells could not be induced to express B7.2 either by receptor cross-linking or by lipopolysaccharide. These differences in the inducible expression of class II and B7.2 appear to be intrinsic to the B cells, as they were retained in purified populations of B-lineage cells and could not be induced in mature B cells by co-culture with bone marrow cells. Furthermore, short-term culture of bone marrow permitted B-cell maturation, which was accompanied by acquisition of responsiveness to the same stimuli as mature, splenic B cells. The inability of immature B cells to show these responses provides a molecular explanation for their reported deficiency in interacting with T cells. Failure of immature B cells to inducibly express B7.2 may also be important for the establishment of self tolerance in the B-cell compartment.
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PMID:Immature B lymphocytes from adult bone marrow exhibit a selective defect in induced hyperexpression of major histocompatibility complex class II and fail to show B7.2 induction. 1088 89

Endotoxin tolerance (ET) has been described as a temporary alteration in the lipopolysaccharide (LPS) response of monocytic cells after an initial LPS exposure with respect to the production of soluble immunomodulators. Apart from the LPS response, monocytic cells play an important role in initiation of the specific immune response as antigen-presenting cells. This study investigated the capacity of human blood monocytes to induce T-cell stimulation in ET. First, the expression of monocyte surface molecules, important for T-cell interaction, was analyzed by flow cytometry. In vitro priming of peripheral blood mononuclear cells with LPS clearly down-regulates major histocompatibility complex class II molecules and the costimulatory molecule CD86. Both changes were dependent on the endogenous interleukin (IL)-10 and less so on the transforming growth factor-beta. In contrast, other accessory molecules on monocytes were only marginally down-regulated (CD58), were not significantly changed during ET (CD40), or even remained up-regulated after initial LPS priming (CD54, CD80). Second, an impact of these phenotypic alterations on the accessory function of monocytes was observed. This was manifested as diminished T-cell proliferation and interferon (IFN)-gamma release in response to the presence of different recall antigens. Neutralizing IL-10 during LPS priming prevented the diminished T-cell IFN-gamma production but had little effect on T-cell proliferation. These data confirm that ET is an appropriate model of the monocyte functional state in immunoparalysis, which is frequently observed in patients after septic shock, trauma, or major surgery.
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PMID:Impaired antigen presentation by human monocytes during endotoxin tolerance. 1089 54

The objective of the present study was to define the afferent arm of the mucosal immune system in the lower female reproductive tract. We report here that antigen presentation by vaginal cells is under hormonal control. When vaginal cells from ovariectomized rats treated with estradiol (0.01-10 microg) were incubated with ovalbumin-specific T cells and ovalbumin, a dose-dependent inhibition of antigen presentation was measured. In time course studies, estradiol given to ovariectomized rats inhibited vaginal cell antigen presentation within 24 h after a single injection, relative to that seen in saline controls. To determine whether changes in antigen presentation were attributable to the effect of estradiol on the number of antigen-presenting cells (APCs) in the vagina, tissues were analyzed by immunohistochemistry. Our findings indicate that estradiol inhibited antigen presentation without affecting the number of major histocompatibility complex class II positive cells and at a time when macrophage/dendritic cells/granulocytes in the vagina increase in response to estradiol treatment. Antibody neutralization studies indicated that antigen presentation by vaginal cells from ovariectomized rats is mediated through class II and involves the expression of transmembrane proteins B7.1 and B7.2. In other studies, vaginal APCs interact with thymus APCs to synergistically enhance antigen presentation under conditions in which vaginal antigen presentation is inhibited by estradiol. Analysis of conditioned media indicates that enhancement of thymus antigen presentation involves the release of a soluble factor(s) into the culture media of vaginal cells. When spleen cells were cocultured with vaginal cells from saline-treated rats, proliferation increased in the presence of concanavalin A and/or phytohemagglutinin and decreased with lipopolysaccharide, relative to spleen cells and mitogen alone. In contrast, when incubated with vaginal cells from estradiol-treated rats, spleen cell proliferation was not affected with concanavalin but was inhibited with phytohemagglutinin and lipopolysaccharide. These studies demonstrate that estradiol regulates antigen presentation by vaginal cells and that vaginal cells, in turn, influence antigen presentation, as well as B and T cell proliferation.
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PMID:Antigen-presenting cells in the female reproductive tract: influence of estradiol on antigen presentation by vaginal cells. 1091 75

The therapeutic potential of dendritic cells loaded with tumour antigens for the induction of effective immune responses against cancer is currently being tested in numerous clinical trials. In most cases, the dendritic cells are generated in vitro from peripheral blood monocytes. Many aspects of dendritic cell-based vaccination have not yet been examined in detail, and homologous mouse model systems may prove very valuable for optimizing clinical procedures. In the murine system, however, dendritic cells are usually isolated from either lymphoid tissues or bone marrow cultures. To date, murine monocyte-derived dendritic cells have been described only sporadically. Here, we describe a culture system for the generation of murine dendritic cells from adherent peripheral blood mononuclear cells by culturing in the presence of granulocyte-macrophage colony stimulating factor and interleukin-4. After 7 days of culture the nonadherent cells were harvested from the cultures. Most of these cells exhibited well-accepted characteristics of mature dendritic cells (e.g. veiled appearance, high expression of major histocompatibility complex class II and CD86) and stimulated vigorous proliferation of allogeneic T cells in a primary mixed leucocyte reaction following stimulation with bacterial lipopolysaccharide. Interestingly, staining the cells for expression of the putative antigen-uptake receptor DEC-205 revealed a distinct bimodal distribution.
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PMID:Characterization of murine dendritic cells derived from adherent blood mononuclear cells in vitro. 1093 81

Activation of macrophages with interferon-gamma (IFN-gamma) and lipopolysaccharide (LPS) leads to increased intracellular resistance to microbes and increased major histocompatibility complex class II-restricted antigen presentation, processes that both use the vacuolar compartment. Despite the requirement of the macrophage vacuolar compartment for microbicidal activities and antigen processing, the rates of endocytosis and membrane trafficking in activated macrophages are not clearly defined. In this study, vacuolar compartment dynamics were analyzed in murine bone marrow-derived macrophages activated with LPS and/or IFN-gamma, conditions that increased macrophage nitric oxide production and resistance to infection by Listeria monocytogenes. Relative to nonactivated cells, activated macrophages showed diminished rates of fluid-phase pinocytosis and phagocytosis and delayed progression of macropinosomes and phagosomes to late endosomes and lysosomes. In contrast to the slowing of membrane trafficking, rates of macropinosome acidification were similar between activated and nonactivated cells. One consequence of this slowed membrane trafficking in activated macrophages was a prolonged exposure of incoming molecules to an acidic nonlysosomal compartment, a condition which may facilitate microbicidal chemistries or antigen processing.
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PMID:Altered membrane trafficking in activated bone marrow-derived macrophages. 1103 69


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