Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Macrophage cytocidal activation requires the sequential impingement on the macrophage of a priming stimulus (interferon [IFN] alpha, beta, or gamma) and a triggering stimulus (such as polyinosinic acid:polycytidylic acid [poly [I:C]] or bacterial lipopolysaccharide). The mechanism of progression from the IFN-primed state to the cytocidal state is poorly understood. By quantifying the level of expression of a gene product (complement component factor B [Bf]) associated with cytocidal activation and through the use of phenotypically distinct populations of macrophages (unprimed and IFN-primed), we have investigated the functional necessity of changes in intracellular concentration of free calcium ions ([Ca2+]i) in signaling the transition from the primed to the cytocidal state. Elevating the [Ca2+]i by incubation of unprimed macrophages with the calcium ionophore, ionomycin, failed to induce the expression of Bf. By contrast, Bf was expressed at high levels when IFN-primed macrophages were exposed to ionomycin, suggesting that priming induced within the macrophages the capacity to respond to a nonspecific change in [Ca2+]i. Quantification of the [Ca2+]i in response to exposure to ionomycin revealed an initial transient elevation, followed by a secondary sustained component. No differences in these changes were observed between unprimed and IFN-primed macrophages. We therefore questioned if changes in [Ca2+]i were also implicated in the transition between the primed and the cytocidal state using the ligand, poly [I:C]. In contrast to ionomycin, incubation of IFN-primed macrophages with poly [I:C] did not sustain measurable increases in [Ca2+]i, yet fully stimulated the transition from the IFN primed to the cytocidal state. However, incubation of IFN-primed macrophages with poly [I:C] in the presence of 1) a Ca2+/ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid buffer calculated to clamp the extracellular concentration of free calcium ions to a value approximately equal to the resting [Ca2+]i; 2) the calcium channel blocker verapamil; or 3) the intracellular Ca2+ antagonists (W-7, W-13, and TMB-8) substantially inhibited the induction of Bf. Collectively, these data support the following conclusions. First, that changes in [Ca2+]i comprise an important element in the induction of progression from the IFN-primed to the cytocidal state. Second, the failure to detect global changes in [Ca2+]i in response to the ligand, poly [I:C], suggests that changes in [Ca2+]i or Ca2+ movement may occur in either a spatially restricted or in an asynchronous cyclical fashion and are not detected by population fluorescence measurements. Third, the source of the relevant Ca2+ is extracellular. Fourth, our findings suggest that priming influences macrophage functional responses at a locus that is distal to the changes in [Ca2+]i, thereby potentially allowing signaling processes to be utilized to initiate different cellular responses.
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PMID:Transmembrane-mediated changes in [Ca2+] are involved in the signaling pathway leading to macrophage cytocidal differentiation: implications of localized changes in intracellular [Ca2+] and of interferon priming on Ca2+ utilization. 162 33

Normal human gingival fibroblasts stimulated in vitro by lipopolysaccharide (LPS) from black pigmented oral Bacteroides species produced cell-free (CF) and cell-associated (CA) thymocyte activating factors (TAF). The LPS from other bacteria, including Escherichia coli and Salmonella species, induced minimum levels of TAF in the cultures. The CF-TAF was partially inhibited by anti-human interleukin (HuIL)-1 beta or HuIL-6 antibody, but not by anti-HuIL-1 alpha antibody. However, complete inhibition of the CF-TAF was not observed upon addition of both anti-HuIL-1 beta and HuIL-6 antibodies. Fibroblasts stimulated with Bacteroides LPS released high levels of CF-IL-6 activity. Recombinant (r) HuIL-6 negligibly exhibited TAF activity even in high doses up to 500 U/ml, although it augmented the TAF activity of rHuIL-1 beta. These findings indicated that the CF-TAF consisted mainly of IL-1 beta, and that IL-6 enhanced TAF activity of IL-1 beta. However, other TAF factor (s) may be present in CF specimens. In contrast to CF-TAF, the CA-TAF was inhibited with anti-HuIL-1 alpha. Recombinant human tumor necrosis factor (rHuTNF) directly stimulated fibroblasts to produce CA-TAF, and it also primed them to enhance CA-TAF induction in response to Bacteroides LPS. On the other hand, natural human interferons (nHuIFN) alpha, beta, and gamma did not induce CF- or CA-TAF in fibroblasts. When fibroblasts were primed with nHuIFN beta or gamma, the CA-TAF production by the cells in response to LPS, but not rHuTNF, was markedly enhanced.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Thymocyte activating factors in human gingival fibroblast cultures stimulated by oral Bacteroides lipopolysaccharides: induction, identification and modification by various cytokines]. 213 6

In the present study we have demonstrated that fibroblasts can generate the inflammatory cytokine interleukin 1 (IL 1) under conditions similar to those abundant in cellular immune responses. Thus, induction of IL 1 requires a sequential two-step protocol which consists of preactivation of mouse embryo fibroblasts (MEF) with crude preparations of T cell or macrophage-derived conditioned media (CM; 72 h), followed by a challenge with lipopolysaccharide (LPS; 24 h). Unstimulated fibroblasts or such cells activated by either CM or LPS produced only low levels of IL 1, while a synergism between both signals was observed for obtaining maximal IL 1-like activity in MEF. Each of a series of individual recombinant lymphokines and cytokines (IL 2, granulocyte/macrophage-colony-stimulating factor, tumor necrosis factor, IL 1 beta and interferons-alpha, beta and gamma) was shown to serve as an efficient priming signal for the induction of IL 1. IL 1-like activity in fibroblasts was detected in cell lysates or associated with the producing-cell membrane but not in culture fluids. Immune-stimulated fibroblasts, activated under such experimental conditions, were shown to actively transcribe mRNA of both IL 1 genes (alpha and beta). For the expression of IL 1-specific mRNA in fibroblasts a single stimulus, provided by either LPS or a lymphokine/cytokine, was sufficient; however, a more intense signal was observed when both stimuli were applied. The IL 1-like biological activity of fibroblast origin was significantly reduced by anti-IL 1 alpha antibodies. Thus, fibroblasts, when activated by immune and bacterial products, generate IL 1 which in turn possibly amplifies cellular immune responses or inflammatory processes in connective tissues.
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PMID:Regulation of interleukin 1 generation in immune-activated fibroblasts. 218 35

Antitumor activity, mitogenicity, and lethal toxicity of chemically synthesized lipid A analogs, acylglucosamine-4- or -6-phosphate with the alpha, beta-hydroxyacyl, acyloxyacyl, or hydroxyacyloxacyl groups at the C-2 and C-3 positions, were examined. Meth A fibrosarcoma cells (5 X 10(5)) were inoculated subcutaneously into BALB/c mice on day 0, and six compounds (50 micrograms/mouse) were administered intravenously on days 7 and 9. Although the antitumor activity of these compounds was weaker than that of natural lipopolysaccharide (LPS) or the synthetic lipid A analog (506) of Escherichia sp type, all groups exhibited tumor inhibition rates of 40% to 50% and delayed tumor growth. Six compounds, with the exception of compound A-173 (with the hydroxytetranoyl group at the C-2 and C-3 positions), were capable of increasing the incorporation of [3H]thymidine into cultured splenocytes of C57BL/6 mice, and caused lethal toxicity in C57BL/6 mice sensitized with galactosamine. However, these compounds had lower toxicity than bacterial LPS (about 500- to 1,000-fold). Compounds A-172 and A-174, which have the same structure except for the C-4 or C-6 position of the phosphate group, exerted similar antitumor activity, mitogenicity, and lethality. The results discussed above indicate that the biologic activity of these compounds correlates with the carbon number of fatty acid but is not affected by the different location of the phosphate group. Furthermore, it seems that the difference between the alpha, beta-hydroxy position of fatty acid and the R or S configuration does not alter the biologic effects.
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PMID:Antitumor activity against Meth A fibrosarcoma and biologic activities of synthetic monosaccharide analogs of lipid A in mice. 236 54

Diseases and losses were registered in dependence on vitamin A supply with 2,035 pigs (6.5-114 kg live weight). The histologic examinations comprised various organs of 72 animals. The content of the main protein fractions as well as antibody titre after supplementing antigenes were determined in the serum of 104 animals. The feeding of a vitamin-A- and carotinefree casein-starch-respectively a Vitamin-A-free cereal-soybeanmeal-diet led to deficiency symptoms after 7-8 respectively 16-19 weeks of experiment particularly in the shape of nervous disturbances and voice affectations. Histologically a hyperplasia and a metaplasia of the epithelium of the big ducts in the salivory gland could be proved. The repletion of a part of the avitaminotic animals by means of oral (500 I.U./kg feed) and parenteral (500,000 to 1,000,000 I.U. i.m.) vitamin A administration is proof of a lack of vitamin A. Vitamin A and provitamin dosage did not influence diseases and losses with the exception of the occurrence of deficiency symptoms. The protein content of the serum as well as that of the globulin fractions alpha, beta, gamma did not change, the albumin content was lower in the groups without vitamin A (p greater than 0.05). Antibody titre against the lipopolysaccharide of salmonella dublin and human gamma globulin were diminished in piglets and fattening pigs fed vitamin A free (p less than 0.05). Taking the criterion of animal health, a vitamin A requirement higher than for growth (250 I.U./kg feed) cannot be derived.
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PMID:[Vitamin A requirements of growing swine. 3. Effect of vitamin A supply on the state of health of piglets and fattening swine]. 240 96

Human blood monocytes isolated by centrifugal elutriation from healthy donors were tested for ability to produce membrane-associated antitumor monokine(s) in response to activation stimuli such as various types of interferon (IFN) and/or synthetic desmethyl muramyl dipeptide (norMDP). IFNs (alpha, beta, and gamma) and norMDP rendered blood monocytes cytotoxic to allogeneic A375 melanoma cells, as assayed by measuring release of [125I]iododeoxyuridine in 72 h. When monocytes were treated with any type of IFN for 16 h, and then fixed with paraformaldehyde, they did not show cytotoxicity to A375 cells, but when they were fixed after treatment with norMDP or lipopolysaccharide they showed significant cytotoxicity to A375 melanoma cells. This membrane-associated antitumor monokine induced by the synergistic actions of suboptimal concentrations of IFN-gamma and norMDP, was cytotoxic to HT-29 colon cancer cells as well as A375 melanoma cells, but not to actinomycin D-treated L-929 cells. The fixed monocyte-mediated cytotoxicity against A375 melanoma cells was completely inhibited by a specific anti-interleukin 1 alpha antiserum, but not by a specific anti-interleukin 1 beta antiserum or monoclonal anti-TNF antibody. These results suggest that membrane-associated interleukin 1 alpha is involved through cell-to-cell contact in the host defense mechanism against cancer.
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PMID:Membrane-associated interleukin 1 alpha as a mediator of tumor cell killing by human blood monocytes fixed with paraformaldehyde. 246 72

Studies indicate that, among a number of other cytokines, interferons (IFN alpha, beta and gamma) are important elements regulating acute as well as chronic inflammatory responses. The role of interferons has been investigated in various experimental models of inflammation, by administration both of interferons and of antibodies that block the biological activity of interferons formed endogenously. The conclusions reached from these experiments clearly indicate that interferons can boost as well as inhibit inflammation. The effects depend on the type of inflammation studied, the time of interferon administration or emergence in the tissue, the type of interferon (alpha/beta or gamma), the dosage, and the presence of other inflammation-controlling cytokines. The effect of blockage of IFN gamma by the systemic administration of neutralising antibodies is particularly clear. Such blockage has been found to profoundly modify local lipopolysaccharide (LPS)-induced inflammation, brain inflammation due to autoimmunity or infection, and shock reactions caused by systemic administration of LPS. Further research on the particular place occupied by interferons in the inflammation-controlling cytokine network holds great promise, not only for better understanding but also for improved therapy of acute and chronic inflammatory disease.
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PMID:The potential role of interferons and interferon antagonists in inflammatory disease. 248 67

Human blood monocytes isolated by centrifugal elutriation from healthy donors were tested for ability to produce membrane-associated IL-1 in response to activation stimuli such as various types of interferons (alpha, beta and gamma) and/or synthetic des-methyl muramyl dipeptide (norMDP). When monocytes were treated with norMDP or lipopolysaccharide (LPS) for 16 hr, they released IL-1 into their culture supernatant. When these activated monocytes were fixed with paraformaldehyde (PFA), they stimulated blastogenic responses of C3H/HeJ mouse thymocytes to PHA, suggesting that membrane-associated IL-1 could be induced by norMDP or LPS. Membrane-associated IL-1 was also found to be induced by the synergistic actions of suboptimal concentrations of rIFN-gamma and nor MDP, but not of rIFN-alpha A or rIFN-beta with norMDP. A specific anti-IL-1 alpha antiserum completely inhibited membrane-associated IL-1 activity, but did not affect the thymocyte-stimulating activity of fixed monocytes. IL-1 alpha was detected by fluorescence staining using the anti-IL-1 alpha antiserum on monocytes fixed after gamma IFN-gamma and norMDP. These results suggest that IFN-gamma may be important in expression of membrane-bound IL-1 alpha by the human blood monocytes responsible for regulation of immune responses in vivo.
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PMID:Induction of membrane-associated interleukin 1 alpha (IL-1 alpha) by synergistic activation of human blood monocytes with interferon gamma and muramyl dipeptide analog. 248 23

The present study examined the effect of cyclosporine (CsA) administered with steroid in vivo on the capacity of peripheral blood mononuclear cells (PBMC) from kidney transplant recipients to generate cytokines and their gene expression at the level of messenger RNA (mRNA). PBMC from CsA-prednisolone (Pred)-treated recipients displayed 66.9% inhibition (54.3 +/- 12.4 IU/ml; N = 42; P less than 0.01) of gamma-interferon (gamma-IFN) production compared with normal individuals (134.6 +/- 18.6 IU/ml; N = 23). Azathioprine (Az)-Pred-treated recipients displayed significantly less inhibition of gamma-IFN generation (96.0 +/- 16.1 IU/ml; N = 22; P less than 0.05) than CsA-treated patients. Macrophages (m phi) from CsA-Pred-treated recipients displayed 60.0% inhibition (5.1 +/- 0.7 U/ml; N = 20; P less than 0.01) of interleukin-1 (IL-1) production compared with normal individuals (13.0 +/- 2.9 U/ml; N = 21). These results were confirmed by the experiments using cDNA probe for gamma-IFN or IL-1 (alpha, beta). High levels of gamma-IFN mRNA in phytohemagglutinin (PHA)-stimulated PBMC or IL-1(beta) mRNA in lipopolysaccharide (LPS)-stimulated m phi were present in normal individuals but not in CsA-treated recipients as judged by hybridization to a cloned human gamma-IFN or IL-1(beta) cDNA probe. These studies demonstrated that combination therapy of CsA with steroid inhibits both gamma-IFN and IL-1 gene expression at the level of mRNA at physiological concentrations.
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PMID:Combination therapy of cyclosporine with steroid inhibits gamma-interferon and interleukin-1 gene expression at the level of mRNA synthesis in vivo. 250 64

Cell-associated and secreted interleukin 1 alpha (IL 1 alpha), IL 1 beta and tumor necrosis factor alpha (TNF-alpha), produced by human mononuclear cells (MNC) in vitro in response to lipopolysaccharide, were measured by radioimmunoassay. After 18 h of incubation, total production of IL 1 alpha in medium containing 1% heat-inactivated serum was two-to-three times higher than IL 1 beta. However, in the presence of 1% serum and 5% fresh plasma, IL 1 alpha and IL 1 beta were produced in similar amounts. Independent of the culture conditions, 90% of the IL 1 alpha remained cell associated whereas 80% of IL 1 beta was extracellular. The kinetics of production and release of IL 1 alpha, beta and TNF-alpha were also studied. IL 1 alpha and TNF-alpha reached maximal levels within 6 h of stimulation, whereas IL 1 beta reached maximal levels between 12 and 16 h. IL 1 alpha remained primarily cell associated (80%) for the first 24 h. After 48 h, extracellular IL 1 alpha exceeded cell-associated levels. IL 1 beta was primarily secreted (80%), appearing in the extracellular fluid within 6 h. TNF-alpha appeared in the extracellular fluid within 1 h of incubation, with less than 10% cell associated at any time during the 48 h of incubation. Although the three cytokines share many biological activities, this study provides evidence that MNC IL 1 alpha is predominantly a cell-associated cytokine acting on a cell-cell basis, whereas IL 1 beta and TNF-alpha are secreted as paracrine mediators.
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PMID:Differences in the synthesis and kinetics of release of interleukin 1 alpha, interleukin 1 beta and tumor necrosis factor from human mononuclear cells. 279 79


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