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

The biological effects of staphylococcal enterotoxins (SE), potentiated by bacterial lipopolysaccharide (LPS), were studied with mice. Control animals survived the maximum dose of either SE or LPS, while mice receiving both agents died. SEA was 43-fold more potent than SEB and 20-fold more potent than SEC1. The mechanism of toxicity was further examined with transgenic mice deficient in major histocompatibility complex class I or II expression. Class II-deficient mice were resistant to SEA or SEB. However, class I-deficient animals were less susceptible to SEA (30% lethality) than wild-type mice (93% lethality). In vitro stimulation of T cells from the three mouse phenotypes by SEA correlated well with toxicity. T cells from transgenic or wild-type mice were similarly responsive to SEA when presented by irradiated, wild-type mononuclear cells. These data confirmed that the toxicity of SE was mainly exerted through a mechanism dependent on the expression of major histocompatibility complex class II molecules. Toxicity was also linked to stimulated cytokine release. Levels in serum of tumor necrosis factor alpha, interleukin-6, and gamma interferon peaked 2 to 4 h after the potentiating dose of LPS but returned to normal within 10 h. Concentrations of interleukin-1 alpha were also maximal after 2 h but remained above the background for up to 22 h. Relative to the levels in mice given only SEA or LPS, the levels in serum of tumor necrosis factor alpha, interleukin-6, and gamma interferon increased 5-, 10-, and 15-fold, respectively, after injections of SEA plus LPS. There was only an additive effect of SEA and LPS on interleukin-1 alpha concentrations.
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PMID:Toxicity of staphylococcal enterotoxins potentiated by lipopolysaccharide: major histocompatibility complex class II molecule dependency and cytokine release. 822 6

T cells can react to self-cells bearing the syngenic major histocompatibility complex class II molecule Ia. Decreased autoreactive T cell responses are associated with cancer. Tumor growth causes syngeneic macrophages (M phi) to suppress autoreactive T cell proliferation by decreasing M phi Ia expression and increasing M phi production of the suppressor molecule prostaglandin E2 (PGE2). Because M phi produce tumor necrosis factor-alpha (TNF-alpha) during cancer, and TNF-alpha stimulates M phi PGE2 synthesis, we determined if TNF-alpha mediates tumor-induced suppression of autoreactive T cell proliferation stimulated by syngeneic M phi. We showed that tumor growth increases TNF-alpha production because tumor-bearing host (TBH) M phi synthesized more TNF-alpha than normal host (NH) M phi when cultured with lipopolysaccharide. Exogenous TNF-alpha increased NH CD4+ autoreactive T cell proliferation stimulated by syngeneic NH M phi but not by TBH M phi. When endogenous TNF-alpha activity was neutralized by anti-TNF-alpha antibody addition, T cell proliferation decreased when stimulated by NH M phi but increased when stimulated by TBH M phi. Kinetic studies showed that TNF-alpha affected M phi-stimulated T cell proliferation during the first few hours (4h) of the 96 h culture time. Indomethacin-treatment allowed TNF-alpha to increase T cell proliferation stimulated by TBH M phi. A PGE2-specific enzyme-linked immunosorbent assay showed that TBH M phi T cell cultures contained significantly more PGE2 than those containing NH M phi, and that exogenous TNF-alpha increased PGE2 production in TBH M phi cultures more than in NH M phi cultures. Short-term (4h) pretreatment of M phi with TNF-alpha increased T cell proliferation stimulated by NH, but not TBH, M phi. However, long-term (16 h) TNF-alpha pretreatment reversed TBH M phi-mediated suppression, suggesting that early suppressor molecular production inhibits synthesis or activity of TNF-alpha-induced stimulatory monokines. Although TNF-alpha is known to increase T cell proliferation, these results show that the tumor-induced increase in M phi TNF-alpha synthesis suppress autoreactive T cell proliferation, which is mediated by PGE2 production.
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PMID:Tumor-induced macrophage tumor necrosis factor-alpha production suppresses autoreactive T cell proliferation. 824 47

Availability of mice with a targeted disruption of the interferon gamma (IFN-gamma) receptor gene (IFN-gamma R0/0 mice) made it possible to examine parameters of macrophage activation in the absence of a functional IFN-gamma receptor. We asked to what extent other cytokines could replace IFN-gamma in the induction of nitric oxide or major histocompatibility complex class II antigen (Ia) expression in peritoneal macrophages. In thioglycollate-elicited macrophages from wild-type mice, tumor necrosis factor (TNF) alone was virtually ineffective in inducing release of NO2- (the endproduct of nitric oxide generation), but TNF enhanced NO2- release in the presence of IFN-gamma. In macrophages from IFN-gamma R0/0 mice, which were unresponsive to IFN-gamma, TNF completely failed to stimulate NO2- release. The stimulatory actions of IFN-alpha/beta on NO2- release were indistinguishable in wild-type and IFN-gamma R0/0 macrophages: IFN-alpha/beta was ineffective on its own, showed marginal stimulation of NO2- release in combination with TNF, and was moderately effective in the presence of lipopolysaccharide. The level of constitutive Ia antigen expression was not significantly different in peritoneal macrophages from wild-type and IFN-gamma R0/0 mice. An increased Ia expression was induced by IL-4 and granulocyte-macrophage colony-stimulating factor in both wild-type and IFN-gamma R0/0 macrophages, but the magnitude of this induction was less than with optimal concentrations of IFN-gamma in macrophages from wild-type mice. IFN-alpha/beta showed only a minor stimulatory effect on Ia expression in both wild-type and IFN-gamma R0/0 macrophages. Simultaneous treatment of wild-type macrophages with IFN-alpha/beta and IFN-gamma reduced the IFN-gamma-induced Ia expression in wild-type macrophages, but IFN-alpha/beta did not show an inhibitory effect on IL-4- or granulocyte-macrophage-colony-stimulating factor-induced Ia expression in either wild-type or IFN-gamma R0/0 macrophages. The important role of IFN-gamma in the regulation of the induced expression of major histocompatibility complex class II antigen was confirmed by showing that after systemic infection with the BCG strain of Mycobacterium bovis resident peritoneal macrophages from IFN-gamma R0/0 mice had a lower level of Ia expression than macrophages from wild-type mice. The inability of other cytokines to substitute fully for IFN-gamma in macrophage activation helps to explain the earlier observed decreased resistance of IFN-gamma R0/0 mice to some infections.
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PMID:Generation of nitric oxide and induction of major histocompatibility complex class II antigen in macrophages from mice lacking the interferon gamma receptor. 834 79

Although tumor growth enhances macrophage (m phi) cytotoxic activity by increasing their tumor necrosis factor-alpha (TNF-alpha) production, increased prostaglandin E2 (PGE2) synthesis reduces most immune responses during tumor growth. Macrophages that do not express major histocompatibility complex class II molecules (Ia- m phi) are the predominant suppressor and cytotoxic population and are more abundant in tumor-bearing hosts (TBHs). This study determined if TBH Ia- m phi s are the major population producing TNF-alpha and PGE2 and if these molecules affect Ia- m phi-mediated suppression of alloantigen-stimulated T cell proliferation. Normal host (NH) and TBH splenic Ia(+)-depleted (Ia-) m phi s synthesized more TNF-alpha than their respective whole populations (WPs) when cultured with lipopolysaccharide and interferon-gamma. TBH Ia- m phi s produced the most TNF-alpha. Northern blot analyses showed that Ia- m phi s had higher amounts of TNF-alpha mRNA expression than their respective WP, and TBH Ia- m phi s expressed the highest amounts of TNF-alpha mRNA. When WP and Ia- NH and TBH m phi s were added to alloantigen-stimulated T cells, suppression of T cell proliferation mediated by Ia- m phi s was greater than by their respective WP. TBH Ia- m phi s were most suppressive. The blockage of PGE2 production reduced suppression mediated by TBH Ia- m phi s more than by all other m phi populations. A PGE2-specific enzyme-linked immunosorbent assay showed that PGE2 production was greater in Ia- m phi- than in WP m phi-containing cultures and greatest in cultures containing TBH Ia- m phi s. Because TNF-alpha enhances T cell responses, its effects on Ia- m phi PGE2-mediated suppression was determined. When TNF-alpha was added to m phi-containing T cell cultures, TNF-alpha directly stimulated NH, but not TBH, Ia- m phi s, which enhanced T cell proliferation. However, inhibiting PGE2 production allowed TNF-alpha to stimulate T cell proliferation in TBH Ia- m phi-containing cultures. Collectively, these data show that Ia- m phi s are the major TNF-alpha- and PGE2-producing cells and that these molecules are partly responsible for the tumor-induced increase in m phi-mediated cytotoxicity and suppression, respectively. TNF-alpha not only mediates cytotoxicity but also counteracts Ia- m phi PGE2-mediated suppression. Although tumor growth increases Ia- m phi TNF-alpha production, enhanced PGE2 production blocks TNF-alpha's stimulatory action on Ia- m phi s, which favors their suppressor function during tumor growth.
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PMID:Tumor growth increases Ia- macrophage synthesis of tumor necrosis factor-alpha and prostaglandin E2: changes in macrophage suppressor activity. 838 10

The retinal pigment epithelial (RPE) cell is a potent regulatory cell within the retina. It helps to maintain normal retinal activity, and following gamma interferon (IFN-gamma) exposure, it may express major histocompatibility complex class II molecules and function as an antigen-presenting cell. Since interleukin-1 (IL-1) and IL-6 are potent cytokines observed in ocular inflammatory processes, we initiated studies to evaluate conditions which enable RPE cells to produce these cytokines. Cultures of human RPE cells from two eye donors were established and characterized, and enzyme immunoassays were employed to screen for IL-1 and IL-6 production. Treatment of RPE cells with lipopolysaccharide (LPS) or recombinant tumor necrosis factor alpha, IL-1, or IFN-gamma resulted in a significant level of secretion of IL-6. In contrast, treatment with recombinant epidermal growth factor, basic fibroblast growth factor, platelet-derived growth factor, or transforming growth factor alpha, or LPS can dramatically augment the secretion of IL-6 by RPE cells. Thus, these inflammatory mediators can act alone or synergistically with IFN-gamma to activate RPE cells and dramatically increase the expression and secretion of IL-6. In contrast, IL-1 was not detected following stimulation with any of the above-mentioned cytokines or LPS. Characterization of IL-6 protein production by RPE cells revealed that 98% of the protein is promptly secreted by the cell, its induction is dependent upon the time and concentration of the stimulant, and the continuous presence of the stimulant is required for IL-6 production. Moreover, Western blot (immunoblot) analysis of secreted proteins revealed that IL-6 was produced in multiple molecular forms.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Synergistic effects of gamma interferon on inflammatory mediators that induce interleukin-6 gene expression and secretion by human retinal pigment epithelial cells. 855 3

The ability of purified B1a (Ly-1 B) and B2 cells to switch immunoglobulin isotype was assessed by limiting dilution analysis in two in vitro culture systems. When stimulated in the presence of interleukins-4 and -5 by either lipopolysaccharide or CD40 ligand, the frequency of IgG1 precursors in the B1a population was at most one third that of IgM precursors. In B2 cells, however, the frequency of IgG1 precursors was up to seven times that of IgM precursors. B1a cells were shown to respond to interleukin-4 by virtue of up-regulating major histocompatibility complex class II expression when exposed to the cytokine, precluding non-responsiveness as a reason for not switching to IgG1. Indeed, interleukin-4 was found to specifically induce transcription of the germ-line IgG1 constant region locus in B1a cells as it did in B2 cells. Collectively these results suggest that the ability of B1 cells to respond to isotype switch commitment factors such as interleukin-4 may be secondary to the production of IgM by these cells.
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PMID:B1 and B2 cells differ in their potential to switch immunoglobulin isotype. 856 28

The present in vivo study showed the expression of nitric oxide synthase-like immunoreactivity in epiplexus cells in the lateral ventricles induced by intracerebral injection of lipopolysaccharide into postnatal rats. Nitric oxide synthase-like immunoreactivity was vigorously expressed in epiplexus cells 1 and 3 days after the lipopolysaccharide injection, but by 7 days post-injection, it became undetectable. The expression of nitric oxide synthase-like immunoreactivity was also observed in some of the choroid epithelial cells. The nitric oxide synthase-like immunoreactivity in these cells appeared to be more intense in the ventricle ipsilateral to the LPS injection than that on the contralateral side. The immunostaining patterns of OX-42 and OX-6 for the detection of complement type 3 receptors and major histocompatibility complex class II antigens respectively paralleled that of anti-nitric oxide synthase, indicating that lipopolysaccharide-induced nitric oxide synthase-like immunoreactivity was primarily in epiplexus cells. Immunoelectron microscopy revealed that the nitric oxide synthase-like immunoprecipitate in epiplexus cells and choroid epithelial cells filled the entire cytoplasm and in some areas associated with the membranes of some of the organelles especially the mitochondria, suggesting that the enzyme is mainly cytosolic. It is speculated that nitric oxide synthase in these cells is involved in the synthesis of nitric oxide. The nitric oxide production, if any, through the enzymatic activity of nitric oxide synthase in epiplexus cells as well as the choroid epithelial cells may be involved in host defense against bacterial endotoxin in the ventricular system of postnatal rat brain.
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PMID:Histochemical demonstration of nitric oxide synthase-like immunoreactivity in epiplexus cells and choroid epithelia in the lateral ventricles of postnatal rat brain induced by an intracerebral injection of lipopolysaccharide. 861 31

An overproduction of proinflammatory cytokines by activated macrophages/monocytes mediates the injurious sequelae of inflammation, septic shock, tissue injury, and cachexia. We recently synthesized a tetravalent guanylhydrazone compound (CNI-1493) that inhibits cytokine-inducible arginine transport and nitric oxide (NO) production in macrophages, and protects mice against lethal endotoxemia and carrageenan-induced inflammation. During these investigations we noticed that CNI-1493 effectively prevented lipopolysaccharide (LPS)-induced NO production, even when added in concentrations 10-fold less than required to competitively inhibit L-arginine uptake, suggesting that the suppressive effects of this guanylhydrazone compound might extend to other LPS-induced responses. Here, we report that CNI-1493 suppressed the LPS-stimulated production of proinflammatory cytokines (tumor necrosis factor [TNF], interleukins 1beta and 6, macrophage inflammatory proteins 1alpha and 1beta) from human peripheral blood mononuclear cells. Cytokine suppression was specific, in that CNI-1493 did not inhibit either the constitutive synthesis of transforming growth factor beta or the upregulation of major histocompatibility complex class II by interferon gamma (IFN-gamma). In contrast to the macrophage suppressive actions of dexamethasone, which are overridden in the presence of IFN-gamma, CNI-1493 retained its suppressive effects even in the presence of IFN-gamma. The mechanism of cytokine-suppressive action by CNI-1493 was independent of extracellular L-arginine content and NO production and is not restricted to induction by LPS. As a selective inhibitor of macrophage activation that prevents TNF production, this tetravalent guanylhydrazone could be useful in the development of cytokine-suppressive agents for the treatment of diseases mediated by overproduction of cytokines.
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PMID:Suppression of proinflammatory cytokines in monocytes by a tetravalent guanylhydrazone. 864 96

We have investigated CD4+ T-cell autoreactivity to normal syngeneic B cells in vitro in chronic experimental Chagas' disease. Resting B cells induced an intense proliferative response and lymphokine secretion by splenic CD4+ T cells from Trypanosoma cruzi-infected (8 months or more of infection) donors, compared to much lower responses by uninfected controls. On the other hand, lipopolysaccharide-activated B cells induced syngeneic CD4+ T-cell activation in both control and infected groups. The observed syngeneic T-B-cell cooperation was bidirectional. In the absence of any exogenous stimulus, CD4+ T cells from T. cruzi-infected animals induced much higher production of all tested immunoglobulin (Ig) isotypes (IgM, IgG1, IgG2a, IgG2b, IgG3) by syngeneic B cells, compared to T cells from uninfected donors. When lipopolysaccharide-treated B cells were used, CD4+ T cells from either control or infected donors enhanced IgG1 and IgG3 production, but only CD4+ T cells of infected origin induced IgG2a production in this system without addition of exogenous gamma interferon. Enhanced T-cell proliferation and Ig production were also observed with highly purified CD4+ T cells and in serum-free medium. Both proliferation and Ig production could be blocked with anti-major histocompatibility complex class II monoclonal antibodies. Enhanced reactivity and help for Ig production were seen only in response to syngeneic BALB B cells and not in response to allogeneic B10 B cells. These results indicate that chronic infection with T. cruzi results in increased CD4+ T-cell reactivity towards syngeneic B cells, which leads to spontaneous Ig production. These autoreactive T cells might play a role in polyclonal autoantibody production in chronic Chagas' disease.
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PMID:Chronic experimental Chagas' disease: functional syngeneic T-B-cell cooperation in vitro in the absence of an exogenous stimulus. 869 26

Glatiramer acetate (previously known as copolymer 1) is a synthetic copolymer of four amino acids that has been approved for use in the treatment of multiple sclerosis. It has been shown to suppress myelin antigen specific T cell activation by competing with these antigens at the major histocompatibility complex class II binding site and by inducing antigen specific suppressor T cells. In this study we investigated the effects of glatiramer acetate on the human monocytic cell line, THP-1, activated by lipopolysaccharide and interferon-gamma as a model for macrophages. At non-toxic concentrations of glatiramer acetate there were dose dependent reductions in the percentage of cells expressing human leukocyte DR and DQ antigen as well as in mean fluorescence intensity by flow cytometry. Production of tumor necrosis factor-alpha and the lysosomal cysteine proteinase cathepsin B were markedly inhibited, but production of interleukin-1 increased. These results suggest that glatiramer acetate might alter macrophage effector function and suggest that further studies in human monocytes and macrophages are warranted.
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PMID:Glatiramer acetate blocks the activation of THP-1 cells by interferon-gamma. 954 1


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