Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although tumor necrosis factor (TNF) is undoubtedly a major mediator of the antitumor and shock-inducing activities of lipopolysaccharide (LPS), the outcome of a challenge with TNF is highly dependent on the presence or absence of other substances or conditions. We have previously shown that to obtain lethality in mice after TNF administration both TNF receptor (TNF-R) types have to be triggered. This is illustrated by the fact that recombinant human (rh) TNF, which is a selective murine (m) TNF-R55 agonist, is not lethal, whereas mTNF, which binds both mTNF-R55 and mTNF-R75, is lethal in mice. Triggering of TNF-R75 is, however, no longer needed when sensitizers such as galactosamine or low doses of LPS or interleukin (IL)-1 are also present. Here, we report that this selective species specificity of TNF is also reflected in patterns of induced IL-6: both rmTNF and rhTNF could induce considerable IL-6 peak levels in the plasma (up to 10 ng/ml) 2 to 3 h after TNF administration. However, only rmTNF was capable of inducing the same pattern of sustained IL-6 levels previously observed after lethal LPS doses, while rhTNF only caused induction of transient IL-6 levels, as found after nonlethal LPS doses. We also observed that the sensitizer IL-1 could complement rhTNF to induce such a sustained IL-6 induction. Since we were interested in sensitizers with a defined mechanism of action, we further investigated the effects of the glucocorticoid and progesterone inhibitor RU38486 on the lethal and IL-6-inducing properties of TNF. We observed that RU38486 closely mimicked IL-1: both had similar effects on IL-6 induction and sensitized mice to the lethal effects of TNF with comparable efficiency and kinetics. Using a monoclonal anti-IL-1R antibody, we finally observed that the effects of RU38486 were most probably not mediated by IL-1. These observations suggest that a glucocorticoid-antagonistic activity might be a key factor in the pathways leading to septic shock and that such activity could be a key target for the pharmacological manipulation of sepsis.
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PMID:The glucocorticoid antagonist RU38486 mimics interleukin-1 in its sensitization to the lethal and interleukin-6-inducing properties of tumor necrosis factor. 153 65

Evidence has previously been presented for an immunomodulatory role of a soluble activity, designated as tumor-derived recognition factor (TDRF), which was produced constitutively by P815 mastocytoma, L 1210 leukemia and other murine tumor targets. TDRF synergized with IFN-gamma and IL-2 to promote TNF-alpha and mRNA synthesis and release by murine macrophages for increased autocrine induction of nitric oxide (NO)-mediated tumor cytotoxicity. We have now further assessed the modulatory role of TDRF on TNF-alpha, TNF receptors (TNF-R) and NOS mRNA synthesis. Macrophages activated by INF-gamma priming and triggering by rTNF-alpha bacterial lipopolysaccharide (LPS) of IL-2 evoked greater NO generation in the presence than in the absence of L1210 targets. TDRF-containing culture fluid from L1210 targets was subsequently confirmed to synergize with IFN-gamma and rTNF-alpha, LPS or IL-2 triggering agents to promote increased TNF-alpha mRNA for autocrine induction of NOS mRNA synthesis with resultant augmentation of NO generation. IFN-gamma selectively upregulated TNF-R1 mRNA expression, whereas either IL-2 or LPS upregulated only TNF-R2 mRNA expression. TDRF combined with IFN-gamma to further upregulate TNF-R1 mRNA and with either IL-2 or LPS to further upregulate TNF-R2, mRNA expression. These findings indicate that TDRF activity synergizes with either IL-2 or LPS triggering agents for enhanced activation of IFN-gamma-primed macrophages by promotion of TNF-alpha and TNF-R mRNA synthesis for autocrine induction of NOS with resultant increased NO-mediated tumor cytotoxicity.
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PMID:Tumor-derived factor synergizes with IFN-gamma and LPS, IL-2 or TNF-alpha to promote macrophage synthesis of TNF-alpha and TNF receptors for autocrine induction of nitric oxide synthase and enhanced nitric oxide-mediated tumor cytotoxicity. 754 21

In order to analyse the physiological relevance of the 55 kDa tumor necrosis factor receptor 1 (TNFR1) and its role in various TNF related pathological conditions, such as septic shock, we have generated mice by gene targeting deficient for TNFR1 expression. The TNFR1-deficient mice are unable to cope with Listeria monocytogenes infections but mount an apparently normal immune response when challenged with Vaccinia or LCMV viruses. They are resistant to the lethal effects of lipopolysaccharide (LPS) after sensitization with D-galactosamine (D-GalN) but remain sensitive to very high doses of LPS given alone. We have analyzed functions relevant to inflammatory processes, such as adhesion, secondary factor release, and proliferation in fibroblasts derived from these mice. We show that the TNFR1 virtually monopolises TNF-mediated signaling in all these situations and that the 75 kDa TNFR2 seems to be largely restricted to an accessory role, which is compatible with the previously established "ligand passing" hypothesis.
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PMID:Phenotypic analysis of TNFR1-deficient mice and characterization of TNFR1-deficient fibroblasts in vitro. 774

Tumour necrosis factor (TNF) elicits multiple biological effects through two distinct cell surface receptors, TNF-R1 (p55) and TNF-R2 (p75). Most TNF-mediated biological responses, such as cell death, gene induction, antiviral activity and cytokine production, have been attributed to TNF-R1 (refs 1-5). Gene targeting of this receptor confirms its role in the lethality attributable to low doses of lipopolysaccharide after sensitization with D-galactosamine; surprisingly, the toxicity of high doses of lipopolysaccharide was unaffected. The function of TNF-R2 is less well understood, although there are data supporting a role in T-cell development and the proliferation of cytotoxic T lymphocytes. To clarify the physiological role of TNF-R2, we have generated mice deficient in this receptor by gene targeting. The TNF-R2-/- mice show normal T-cell development and activity, but we find that they have increased resistance to TNF-induced death. Additionally, such mice injected subcutaneously with TNF show a dramatic decrease in tissue necrosis, indicating that this receptor plays a role in the necrotic effects of TNF.
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PMID:Decreased sensitivity to tumour-necrosis factor but normal T-cell development in TNF receptor-2-deficient mice. 799 Sep 30

We investigated the effects of a single bacterial lipopolysaccharide (LPS) injection in vivo on the gene expression of tumor necrosis factor-alpha (TNF) and its receptors: TNF receptor type I (TNF-R 55 kDa or TNF-R1) and TNF receptor type II (TNF-R 75 kDa or TNF-R2) in various tissues and white blood cells. While TNF mRNA rapidly accumulated in most tissues, TNF-R1 and TNF-R2 mRNA levels were found to be differentially regulated in lung, spleen, lymph nodes and white blood cells. In most cases, TNF-R mRNA levels did not parallel TNF mRNA levels. These observations indicate that TNF-R of both types of capable of modulating the host response to LPS, not only by shedding of their extracellular domains, but also by strict regulation of their gene expression.
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PMID:Modulation of the transcripts for tumor necrosis factor-alpha and its receptors in vivo. 812 44

Tumour necrosis factor (TNF), jointly referring to TNF alpha and TNF beta, is a central mediator of immune and inflammatory responses; its activities are mediated by two distinct receptors, TNFR1 (p55) and TNFR2 (p75) (reviewed in refs 1-3). The cytoplasmic domains of the TNFRs are unrelated, suggesting that they link to different intracellular signalling pathways. Although most TNF responses have been assigned to one or the other of the TNF receptors (mostly TNFR1), there is no generally accepted model for the physiological role of the two receptor types. To investigate the role of TNFR1 in beneficial and detrimental activities of TNF, we generated TNFR1-deficient mice by gene targeting. We report here that mice homozygous for a disrupted Tnfr1 allele (Tnfr1(0)) are resistant to the lethal effect of low doses of lipopolysaccharide after sensitization with D-galactosamine, but remain sensitive to high doses of lipopolysaccharide. The increased susceptibility of Tnfr1(0)/Tnfr1(0) mutant mice to infection with the facultative intracellular bacterium Listeria monocytogenes indicates an essential role of TNF in nonspecific immunity.
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PMID:Mice lacking the tumour necrosis factor receptor 1 are resistant to TNF-mediated toxicity but highly susceptible to infection by Listeria monocytogenes. 839 24

Tumor necrosis factor alpha(TNF alpha), a proinflammatory cytokine secreted predominantly by monocytemacrophages, interacts with two cell-surface receptors: TNF-R55 and TNF-R75. Few studies have been devoted to their modulation on human alveolar macrophages (AM). Both source and target of TNF(alpha), AM also release its inhibitors, the soluble receptors, following the cleavage of the extracellular domain of TNF-R55 and TNF-R75. Because in vivo AM are subject to activation by exogenous or endogenous stimuli, we analyzed the release of both receptors into the cell culture supernatant in response to lipopolysaccharide (LPS), phorbol myristate acetate (PMA), and cytokines such as interleukin 2(IL-2), IL-4, IL-6, granulocyte-macrophage colony-stimulating factor (GM-CSF), and interferon gamma (IFN-gamma). Results were compared with those obtained on peripheral blood monocytes (Mo), and the role of receptor recycling was investigated using inhibitors such as monensin and chloroquine. In our culture conditions, basal release by unstimulated AM amounted to 0.3 +/- 0.1 and 0.5 +/- 0.1 ng/ml for TNF-sR55 and TNF-sR75, respectively. In the same conditions, Mo released 1.2 +/- 1.2 ng/ml of TNF-sR55 and 5.1 +/- 0.1 ng/ml of TNF-sR75. PMA slightly increased mRNA expression and release of TNF-sR55, but those of TNF-sR75 were enhanced approximately 4-fold. After 24 h of culture, the release of TNF-sR75 was 2.5-fold higher on Mo than on AM. Of the cytokines tested on AM, IFN-gamma increased the release of TNF-sR75 3-fold, but that of TNF-sR55 only between 1.5- and 2-fold. GM-CSF enhanced them to a lower extent (approximately 1.5-fold). Shedding occurred despite the presence of chloroquine, monensin and colchicine, suggesting that cleavage takes place on the cell surface rather than after internalization. Addition of colchicine increased the release of TNF-sR75 induced by LPS and IFN-gamma, but not by PMA. In conclusion, Mo and AM differ in their ability to release TNF(alpha) and TNF-sR. On AM the release of each receptor appears to be regulated separately. Finally, IFN-gamma was among the most efficacious cytokines to induce the release of both receptors, with TNF-sR75 being more liable to shedding. Thus, the two TNF-R seem to be ruled by separate mechanisms and to differ in terms of release sensitivity.
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PMID:Tumor necrosis factor soluble receptor 75: the principal receptor form released by human alveolar macrophages and monocytes in the presence of interferon gamma. 884 79

The involvement of CD14 in lipopolysaccharide (LPS) recognition and signaling has been demonstrated in several studies. For this reason, we investigated whether the resistance of Lpsd mice to LPS might be related to an impaired CD14 expression. We compared the in vivo and in vitro expression of CD14 in Lpsn (LPS sensitive) and Lpsd mice, and its modulation by LPS, killed gram-negative and gram-positive bacteria and double-stranded (ds)RNA. Untreated Lpsn and Lpsd cultured macrophages (M phi), expressed similar amounts of CD14 mRNA and membrane-bound (m)CD14. LPS enhanced CD14 expression only in Lpsn M phi, while all bacteria, or dsRNA, enhanced CD14 in Lpsn and Lpsd M phi. Similarly, in vivo administration of LPS induced or enhanced CD14 mRNA in different organs of Lpsn mice only, while bacteria or dsRNA in both types of mouse. Furthermore, exogenous recombinant tumor necrosis factor (TNF) induced in vivo and in vitro enhanced CD14 expression in Lpsn, Lpsd and also in TNF receptor 2-deficient (TNFR2-/-) mice, but failed to do so in TNFR1-/- mice, showing that TNFR1 mediates the effect of TNF on CD14. However, LPS, bacteria and dsRNA induced CD14 in both TNFR2-/- and TNFR1-/- mice to a similar extent, revealing that this induction does not require TNF signaling.
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PMID:Induction of CD14 expression in Lpsn, Lpsd and tumor necrosis factor receptor-deficient mice. 892 56

Tumor necrosis factor (TNF) is a central mediator of immune and inflammatory responses. Its activities have been shown to be mediated by two distinct receptors, TNFR1 (p55) and TNFR2 (p75). The cytoplasmic domains of both TNF receptors are unrelated, suggesting that they link to different intracellular signaling pathways. To determine their role in vivo in lipopolysaccharide (LPS)- and TNF-induced skin inflammatory necrosis, TNFR1-, TNFR2-, and TNF lymphotoxin-alpha (LT alpha)-deficient mice were used. Skin abscesses were experimentally induced with local application of TNF or LPS. Large macroscopic ulcerations were observed in TNF-injected wild-type animals and to a slightly lesser extent in TNFR2-deficient mice with tissue destruction in both cases extending deep into the dermis. Tissue destruction was accompanied by an intense immune infiltrate composed mainly of neutrophils, lymphocytes, and macrophages. TNFR1-deficient and TNFR1/TNFR2-double-deficient mice, however, did not exhibit any ulceration and showed only a very mild inflammatory infiltrate. In TNF/LT alpha-double ligand0-deficient animals, a moderate epidermal necrosis was observed with a reduced inflammatory infiltrate compared to wild-type animals. As with TNF injections, subcutaneous injection of LPS induced a comparable pattern of skin necrosis in wild-type and TNF receptor mutant mice, yet a slightly more acute inflammatory level was observed regardless of the type of animal tested. As found for TNF-induced skin necrosis, the extent of LPS-induced skin necrosis was reduced in TNF/LT alpha-deficient mice compared to wild-type animals. The present data strongly suggest that TNFR1, rather than TNFR2, is engaged in LPS- and TNF-induced skin necrosis and highlight the predominant role played by TNF in LPS-induced inflammatory diseases.
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PMID:Tumor necrosis factor (TNF)-induced cutaneous necrosis is mediated by TNF receptor 1. 914 75

The arthritogenic activities of tumor necrosis factor (TNF) and its p55TNF-receptor (R) have been well documented in experimental animal models of arthritis, and in transgenic mice expressing wild-type or mutant transmembrane human TNF proteins in their joints. In this study we show that chronic inflammatory arthritis also develops in transgenic mice made to overexpress a mutant transmembrane from of the murine TNF protein (muTNF delta 1-12) which is known to utilize efficiently both the p55 and the p75TNFR. Cross-breeding of the transgene into a TNF knockout background did not alter development of disease. Analysis of TNF bioactivity in sera from lipopolysaccharide-stimulated mice or ex vivo macrophage cultures demonstrated that the muTNF delta 1-12 protein accumulates on the cell surface and is not processed to bioactive soluble TNF, indicating that transmembrane TNF is by itself sufficient to mediate pathogenesis of arthritis. Furthermore, using TNFR knockout mice, it is shown that development of transmembrane TNF-mediated arthritis requires the presence of the p55TNFR but is significantly delayed in the absence of the p75TNFR, suggesting a positive cooperation between the two TNFR in the arthritogenic process. These results indicate that blocking the activities of both soluble and transmembrane TNF may be required to effectively neutralize the pathogenic potential of this cytokine in arthritis.
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PMID:A murine transmembrane tumor necrosis factor (TNF) transgene induces arthritis by cooperative p55/p75 TNF receptor signaling. 936 14


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