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 effects of human interferon gamma (IFN gamma) encapsulated into liposomes were investigated in vitro. Monocytes were induced to release a cytotoxic factor with either IFN gamma encapsulated into liposomes, free IFN gamma or lipopolysaccharide (LPS). If IFN gamma was applied in the liposomal form, less IFN activity was required to stimulate monocytes. Most of the cytotoxic factor was secreted during the first 4 h of stimulation. The cytotoxic factor in supernatants from PMNLs was completely neutralized by a monospecific polyclonal antiserum to tumor necrosis factor (TNF). Combining subthreshold doses of IFN gamma liposomes or IFN gamma with lipopolysaccharide synergistically enhanced the release of TNF. In fluorescence analysis, altered expression of the class II HLA-DR antigen on LeuM3 positive monocytes was induced with IFN gamma liposomes as well as with IFN gamma. Not only monocytes but also natural killer (NK) cells were stimulated to higher cytotoxicity by IFN gamma liposomes in a dose-dependent manner. In comparison with IFN gamma, the same amount of activity was necessary for adequate stimulation of NK-cells against the K562 target cells. Furthermore, the antiproliferative effects of IFN gamma liposomes and free IFN gamma on several human tumor cell lines was compared. Among several cell lines tested, U937 and A549 turned out to be sensitive to IFN gamma, and both cell lines reacted with 50% growth inhibition at a lower amount of gamma presented by liposomes than in the free form. These data show production of IFN gamma liposomes which possess immunomodulatory and antiproliferative activity in vitro. In several of the test systems studied, liposome-encapsulated IFN gamma was more effective than free IFN gamma.
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PMID:Interferon gamma encapsulated into liposomes enhances the activity of monocytes and natural killer cells and has antiproliferative effects on tumor cells in vitro. 211 74

Activated macrophages mediate cytotoxicity against tumor targets and thus may modulate development and growth of metastatic tumor cells. Macrophage colony stimulating factor (M-CSF) has a potential role in activating mature macrophages to a cytotoxic state. We employed a murine Kupffer cell (KC) model of cytotoxicity against a tumor necrosis factor (TNF) - sensitive murine colon adenocarcinoma cell line (MCA26) to evaluate the ability of recombinant human M-CSF (rhM-CSF) 1) to act alone as a KC-activating agent and 2) to enhance KC cytotoxicity against MCA26 cells in association with known macrophage activating compounds. rhM-CSF produced a dose-dependent increase in TNF release by KC in vitro with a parallel increase in MCA26 killing. KC activated by rhM-CSF produced less TNF and concomitantly demonstrated a lower cytotoxicity against MCA26 cells when compared with KC activated by gamma interferon (gamma IFN) with or without lipopolysaccharide (LPS). M-CSF did not act in a synergistic fashion with gamma IFN and LPS to increase TNF secretion or cytotoxicity against MCA26 cells. rhM-CSF thus acts as a single agent capable of activating murine KC to a cytotoxic state but does not cooperate with classical priming/triggering signals to achieve KC activation.
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PMID:Human recombinant macrophage colony stimulating factor activates murine Kupffer cells to a cytotoxic state. 211 71

Monocytes activated by lipopolysaccharide (LPS) and interferon gamma (IFN gamma) rapidly secrete a number of monokines with different functional properties. Interleukin-4 (IL-4), a T-cell derived cytokine, has been shown to reduce the production of monokines with cytostatic activity for tumor cells, chemotactic activity for monocytes, and factors that stimulate thymocyte proliferation. This latter activity is mediated by a number of monokines like IL-1, tumor necrosis factor alpha (TNF alpha), and IL-6. To elucidate which cytokines produced by monocytes are controlled by IL-4, we tested the effect of IL-4 on the secretion of IL-1 alpha, IL-1 beta, TNF alpha, and IL-6 induced by LPS or IFN gamma. IL-4 was found to inhibit the secretion of IL-1 beta and TNF alpha by activated monocytes almost 100%. The secretion of IL-6 was found to be reduced 70% to 85% in the presence of IL-4, whereas there was no effect on the secretion of IL-1 alpha (IL-1 alpha is mainly cell-associated). Time-course experiments demonstrate that IL-4 reduces the secretion of monokines for a prolonged period of time (greater than 40 hours). The reduced secretion of IL-1 beta and TNF alpha was specifically induced by IL-4 because anti-IL-4 antiserum completely restored normal monokine production. These data suggest that IL-4 plays a role in the regulation of immune responses by reducing the production of functionally important monokines.
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PMID:Interleukin-4 (IL-4) inhibits secretion of IL-1 beta, tumor necrosis factor alpha, and IL-6 by human monocytes. 211 29

Cisplatin, doxorubicin and daunorubicin (drugs which intercalate with DNA) influenced the membrane-bound procoagulant potential of murine thioglycollate-induced peritoneal exudate (TG-PEC) macrophages and the monocytoid cell line WEHI 265, whereas the antimetabolites 5-fluorouracil and methotrexate had no effect. Enhanced procoagulant was not caused by non-specific toxicity of these agents. Cisplatin directly increased the procoagulant expressed on WEHI 265 cells, whereas MPCA on TG-PEC was enhanced only when cisplatin was combined with a second stimulant, either bacterial lipopolysaccharide (LPS) or interferon (IFN gamma). WEHI 265 cells failed to respond to the anthracycline drugs, either alone or in combination with LPS, whereas they enhanced the IFN gamma response. Doxorubicin and daunorubicin increased the LPS response of TG-PEC by approximately 4-fold and the IFN gamma response by approximately 10-fold. Pulsing experiments suggested that the anthracyclines enhanced procoagulant expression by a mechanism different from cisplatin. Daunorubicin primed TG-PEC within 4 hr to respond to low levels of LPS, whereas either LPS or cisplatin primed these cells to respond to cisplatin or LPS respectively. Furthermore, the procoagulant expressed by TG-PEC stimulated by LPS/cisplatin had properties of tissue factor (TF: 50% total activity) and Factor VIIa (50% total procoagulant)-like activities, whereas the predominant procoagulant on LPS/anthracycline activated TG-PEC was TF-like (70% total activity) with weak Factor VIIa and prothrombinase-like properties.
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PMID:Induction of macrophage procoagulant expression by cisplatin, daunorubicin and doxorubicin. 212 Jan 34

Although macrophage activation is induced in a complex manner by signals such as interferon-gamma (IFN gamma) and bacterial lipopolysaccharide (LPS) and depends on alterations in levels of specific proteins due to differences in gene expression, the complexity of gene regulation during macrophage activation in regard to multiple signals is not fully appreciated. To probe this question, we selected four model genes encoding for tumor necrosis factor (TNF), interleukin-1 (IL-1), and the immediate early genes JE and KC. After analyses of Northern blots for specific mRNA, LPS was found to enhance levels of mRNA for IL-1, TNF, JE, and KC. IFN gamma initiated heightened mRNA levels for JE but did not alter specific mRNA for IL-1, TNF, or KC. When IFN gamma and LPS were combined, additive effects on levels of specific mRNA for JE, enhancement of mRNA for TNF, suppressed mRNA for KC, and no effect on mRNA for IL-1 were observed. When transcription of these genes was assessed by nuclear "run on" experiments, LPS increased transcription of KC and TNF but not of IL-1 or JE, implying that the increased levels of mRNA for JE and IL-1 were attributable to increased stability of mRNA. Likewise, IFN gamma did not initiate transcription of JE. When IFN gamma and LPS were given together, IFN gamma enhanced the LPS-induced transcription of TNF and KC, suggesting decreased stability of mRNA for KC. A distinct pattern of regulation for each of the four genes was thus observed. Taken together, the data suggest that gene regulation in macrophage activation represents a complex response of enhanced and suppressed transcription and mRNA stability, the precise pattern of which depends on the stimuli given to the macrophages and the gene examined.
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PMID:Gene regulation in macrophage activation: differential regulation of genes encoding for tumor necrosis factor, interleukin-1, JE, and KC by interferon-gamma and lipopolysaccharide. 212 82

The present study demonstrates that murine dermal fibroblasts produce nitrite (NO2-) and nitrate (NO3-) upon treatment with interferon gamma (IFN-gamma). This formation is dependent on L-arginine and can be inhibited by the L-arginine analogue NG-monomethyl-L-arginine. The effect of IFN-gamma is drastically increased by cotreatment with tumor necrosis factor alpha (TNF-alpha), interleukin 1 (IL-1), or lipopolysaccharide (LPS). The tested cytokines also induce formation of tetrahydrobiopterin in murine fibroblasts. Inhibition of guanosine triphosphate-cyclohydrolase I, the key enzyme of tetrahydrobiopterin de novo synthesis with 2,4-diamino-6-hydroxy-pyrimidine, leads to decreased formation of NO2- and NO3-. This effect can be reversed by addition of sepiapterin, which provides tetrahydrobiopterin via a salvage pathway. Methotrexate, which inhibits the salvage pathway, blocks the restoration of NO2- and NO3- production by sepiapterin. The cytotoxic effect of combinations of IFN-alpha with TNF-gamma, IL-1, or LPS is attenuated by inhibition of tetrahydrobiopterin synthesis. These results show that intracellular concentrations of tetrahydrobiopterin control the amount of NO2- and NO3- produced in situ and suggest that the role of cytokine-induced tetrahydrobiopterin synthesis is to provide cells with the active cofactor for production of nitrogen oxides.
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PMID:Tetrahydrobiopterin-dependent formation of nitrite and nitrate in murine fibroblasts. 212 51

Bacterial lipopolysaccharide (LPS)-induced production of three known endogenous pyrogens, interferon alpha (IFN-alpha), interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF-alpha) was studied during in vitro differentiation of human peripheral blood monocytes. In freshly seeded cells, secretion of IL-1 and TNF-alpha, but not IFN-alpha were readily induced by LPS. After 24 hr and for up to 14 days of culture, monocytes became irreversibly tolerant to LPS for the release of IL-1. IFN-alpha secretion was not induced by LPS in cells cultured for up to 8 days. Monocytes also became tolerant to LPS for TNF-alpha production 48 hr after an initial stimulation with LPS. This tolerant state, however, was transient, lasting from 6 to 8 days, after which competence for TNF secretion resumed. These observations demonstrate that regulation of production of IL-1, TNF-alpha and IFN-alpha by human mononuclear phagocytes is mutually independent, related to the stage of cell differentiation and modulated by cell stimulation. Since in vitro tolerance to LPS mimics the in vivo tolerance to LPS with respect to fever, we speculate that they are closely related.
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PMID:Tolerance to endotoxin in vitro: independent regulation of interleukin-1, tumor necrosis factor and interferon alpha production during in vitro differentiation of human monocytes. 220 68

A promonocytic cell model was used to investigate cytokine gene transcription in U937 and U9-IIIB cells chronically infected with human immunodeficiency virus type 1 (HIV-1). The production of interferon (alpha-1 interferon [IFN-alpha 1], IFN-alpha 2, and IFN-beta), interleukin (interleukin 1 alpha [IL-1 alpha], IL-1 beta, and IL-6), and tumor necrosis factor alpha (TNF-alpha) mRNA was characterized by quantitative polymerase chain reaction mRNA phenotyping in U937 and U9-IIIB cells following coinfection with Sendai paramyxovirus or stimulation with lipopolysaccharide (LPS). Chronic HIV-1 infection of U9-IIIB cells resulted in a low constitutive level of transcription of TNF and IL-1 genes but not IFN genes; however, when the cells were coinfected with Sendai virus, 10- to 20-fold higher levels of IFN-beta, IL-1 beta, IL-6, and TNF-alpha mRNA were observed in U9-IIIB cells than in similarly induced U937 cells. The enhanced levels of cytokine RNA in virus-infected U9-IIIB cells were also accompanied by higher levels of IFN antiviral activity and TNF secretion than in U937 cells. Transcript levels for IFN-alpha 1 and IFN-alpha 2 were equivalently induced in virus-infected U937 and U9-IIIB cells, indicating that a generalized derepression of cytokine gene expression did not occur as a consequence of HIV-1 infection. When LPS was used as an inducer, a distinct pattern of cytokine gene expression was detected in U9-IIIB cells. TNF-alpha and IL-1 beta but not IFN-alpha or IFN-beta transcripts were induced by LPS. These results suggest that HIV-1 infection of promonocytic cells may prime or sensitize cells such that subsequent antigenic challenge leads to coordinate enhancement of cytokine gene expression.
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PMID:Coordinate enhancement of cytokine gene expression in human immunodeficiency virus type 1-infected promonocytic cells. 224 88

Human peripheral blood mononuclear cells activated with concanavalin A (Con A) or lipopolysaccharide (LPS) produce, respectively, lymphokines (LK) of 50,000 Mr or monokines (MK) of 20,000 Mr that inhibit the growth and collagen production of cultured human dermal fibroblasts. Because antigenic typing of the antiviral activity of these LK and MK preparations revealed that LK contained mainly gamma interferon (IFN-gamma), and MK, primarily IFN-beta, we investigated if any of the fibroblast-inhibiting activities could be attributed to human IFN. Unlike LK and MK, which act within 24 h to inhibit the growth of subconfluent foreskin and adult dermal fibroblasts, samples of purified, natural derived IFN-alpha, -beta, and -gamma and recombinant DNA-derived IFN-alpha 2 and -gamma were ineffective inhibitors at 24 h and required 48-72 h to significantly inhibit growth. However, all IFN did mimic LK/MK action in causing concentration-dependent inhibition of collagen production by confluent fibroblast microcultures. Furthermore, the collagen production-inhibiting activity of Con A-induced LK supernatant and its 50,000 Mr fraction was completely suppressed by 10(3) neutralizing U/ml of either polyclonal or monoclonal antibody to IFN-gamma, while polyclonal antibodies to IFN-alpha and -beta had no effect. Similarly, the collagen production-inhibiting activity of LPS-induced MK supernatant and its 20,000 Mr fraction was suppressed by polyclonal anti-IFN-beta but not by anti-IFN-alpha or -gamma. Anti-IFN failed to reverse early-acting LK or MK growth-inhibiting activities. These data suggest collagen production-inhibiting LK and MK are IFN-gamma and IFN-beta, respectively, and that early acting, growth-inhibiting LK and MK are not IFN.
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PMID:Gamma interferon is the lymphokine and beta interferon the monokine responsible for inhibition of fibroblast collagen production and late but not early fibroblast proliferation. 241 May 28

Although peritoneal resident macrophages (PRM) or peritoneal exudate macrophages (PEM) were activated by lipopolysaccharide (LPS) to kill tumor cells in vitro, lung macrophages (LM) obtained by mincing lung tissues or by harvesting bronchial lavage were not activated by LPS under any experimental conditions, i.e., different LPS concentrations, incubation times and cytotoxicity assay methods. The unresponsiveness of LM to LPS was seen in all of the mouse strains tested. Treatment of LM with indomethacin did not affect the unresponsiveness, although it greatly augmented the cytotoxicity of PRM stimulated with LPS. LM treated in vitro with crude lymphokines (LK) did not show cytotoxicity, but became sensitive to LPS and cytotoxic for tumor cells. LM treated first with crude LK and then with LPS were cytotoxic, but LM treated first with LPS and then with crude LK were not. The ability of crude LK to render LM responsive to LPS was neutralized by rabbit anti-mouse gamma interferon (IFN-gamma) antiserum but not by anti-mouse IFN-(alpha + beta) antiserum. LM treated with recombinant murine IFN-gamma became responsive to LPS and showed cytotoxicity. LM were resistant to direct toxicity of LPS under conditions in which significant populations of PRM and PEM died. However, LM became sensitive to direct toxicity of LPS by treatment with crude LK or recombinant murine IFN-gamma. Fluorescence microscopy showed that almost all PRM and PEM were stained with fluorescein isothiocyanate (FITC)-LPS, while less than 5% of the LM were stained. Instead, approximately 60% of the LM treated with the crude LK or recombinant IFN-gamma for 20 h were stained with FITC-LPS. Fluorescence-activated cell sorter (FACS) analysis confirmed this result. The staining of IFN-gamma treated LM with FITC-LPS was inhibited by polymyxin B or unlabeled LPS. These results suggest that the defective responsiveness of LM to LPS is due to the lack or very low expression of LPS-binding sites on the cell surface and that in vitro treatment with IFN-gamma brings about the expression of them and renders LM responsive to LPS.
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PMID:Lack of binding of bacterial lipopolysaccharide to mouse lung macrophages and restoration of binding by gamma interferon. 241 87


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