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)

Recombinant mouse interleukin 10 (IL-10) was exceedingly potent at suppressing the ability of mouse peritoneal macrophages (m phi) to release tumor necrosis factor alpha (TNF-alpha). The IC50 of IL-10 for the suppression of TNF-alpha release induced by 0.5 microgram/ml lipopolysaccharide was 0.04 +/- 0.03 U/ml, with as little as 1 U/ml suppressing TNF-alpha production by a factor of 21.4 +/- 2.5. At 10 U/ml, IL-10 markedly suppressed m phi release of reactive oxygen intermediates (ROI) (IC50 3.7 +/- 1.8 U/ml), but only weakly inhibited m phi release of reactive nitrogen intermediates (RNI). Since TNF-alpha is a T cell growth and differentiation factor, whereas ROI and RNI are known to inhibit lymphocyte function, it is possible that m phi exposed to low concentrations of IL-10 suppress lymphocytes. m phi deactivated by higher concentrations of IL-10 might be permissive for the growth of microbial pathogens and tumor cells, as TNF-alpha, ROI, and RNI are major antimicrobial and tumoricidal products of m phi. IL-10's effects on m phi overlap with but are distinct from the effects of the two previously described cytokines that suppress the function of mouse m phi, transforming growth factor beta and macrophage deactivation factor. Based on results with neutralizing antibodies, all three m phi suppressor factors appear to act independently.
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PMID:Macrophage deactivation by interleukin 10. 174 84

Expression of the interleukin 10-encoding (IL-10) mRNA by ovine (ov-) cells, in response to mitogenic stimulation, was assessed by Northern blot and polymerase chain reaction (PCR) analyses using a human (hu) IL-10 cDNA probe and oligodeoxyribonucleotide primers based on homologous regions of the human and murine IL-10 cDNA sequences. A 315-bp cDNA generated by the PCR analysis was cloned and used to screen a lipopolysaccharide-stimulated alveolar ov-macrophage cDNA library. The full-length ov-cDNA sequence isolated translates to a protein of 177 amino acids (aa) with a predicted 18-aa leader sequence and molecular mass of 20,165 Da. Expression in a mammalian system demonstrated that the ov-cDNA encoded a protein with the expected IL-10 biological activity. Both recombinant huIL-10 and supernatants from COS cells transfected with an expression vector containing the ovIL-10 cDNA inhibited production of IL-1 and tumour necrosis factor-alpha by ov-alveolar macrophages. Genomic DNA analysis indicated ovIL-10 exists as a single gene within the ov-genome.
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PMID:Cloning and characterisation of an ovine interleukin-10-encoding cDNA. 762 47

Clones encoding porcine interleukin 10 (IL-10) were isolated from a cDNA library produced from phytohemagglutinin-activated pig peripheral blood mononuclear cells. The porcine IL-10 nucleotide sequence was found to be highly homologous to the rat, mouse, and human IL-10 counterparts and to one of the open reading frames from the Epstein-Barr virus. In addition, pig IL-10 caused inhibition of gamma-interferon gene transcription as determined by a bioassay. To investigate the possible immunomodulatory role of IL-10, its expression during the induction of tolerance to kidney allografts by cyclosporin A in miniature swine was also investigated. Delayed expression and higher levels of IL-10 were observed in tolerant animals compared with animals rejecting their allografts. Since tolerance is achieved by a short course of cyclosporin A, we have also studied the in vitro effect of this drug on IL-10 gene transcription in blood mononuclear cells and have found that cyclosporin A inhibits IL-10 gene activation in T cells but does not interfere with IL-10 transcription in lipopolysaccharide-activated cells. These results suggest that the overexpression of IL-10, observed in cell populations infiltrating grafts from tolerant animals, may be a function of monocytes and/or B cells.
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PMID:Molecular identification of porcine interleukin 10: regulation of expression in a kidney allograft model. 770 27

Anticytokine therapies have been promulgated in gram-negative sepsis as a means of preventing or neutralizing excessive production of proinflammatory cytokines. However, systemic administration of cytokine inhibitors is an inefficient means of targeting excessive production in individual tissue compartments. In the present study, human gene transfer was used to deliver to organs of the reticuloendothelial system antagonists that either inhibit tumor necrosis factor-alpha (TNF-alpha) synthesis or block its interactions with cellular receptors. Mice were treated intraperitoneally with cationic liposomes containing 200 micrograms of either a pCMV (cytomegalovirus)/p55 expression plasmid that contains the extracellular domain and transmembrane region of the human p55 TNF receptor, or a pcD-SR-alpha/hIL-10 expression plasmid containing the DNA for human interleukin 10. 48 h later, mice were challenged with lipopolysaccharide (LPS) and D-galactosamine. Pretreatment of mice with p55 or IL-10 cDNA-liposome complexes improved survival (p < 0.01) to LPS-D-galactosamine. In additional studies, intratracheal administration of IL-10 DNA-liposome complexes 48 h before an intratracheal LPS challenge reduced pulmonary TNF-alpha levels by 62% and decreased neutrophil infiltration in the lung by 55% as measured by myeloperoxidase activity (both p < 0.05). Gene transfer with cytokine inhibitors is a promising option for the treatment of both the systemic and local sequelae of septic shock.
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PMID:Human tumor necrosis factor receptor (p55) and interleukin 10 gene transfer in the mouse reduces mortality to lethal endotoxemia and also attenuates local inflammatory responses. 776 15

Current evidence suggests that the gut is the chief portal of entry for organisms of the Mycobacterium avium complex (MAC) in AIDS patients. Bacterial invasion of intestinal mucosa presumably occurs through epithelial cells, and M cells in the Peyer's patches, where the bacteria have contact with immunocompetent cells such as macrophages and T and B lymphocytes. As mucosal macrophages are probably the first line of defense against MAC, we examined their ability to inhibit intracellular growth of MAC when properly stimulated. Mouse intestinal macrophages were purified, infected with MAC 101, serovar 1, and MAC 86-2686, serovar 16, and subsequently stimulated with recombinant tumor necrosis factor alpha (TNF-alpha), gamma interferon (IFN-gamma), granulocyte-macrophage colony-stimulating factor (GM-CSF), or macrophage colony-stimulating factor (M-CSF). Viable intracellular bacteria were quantitated at 24 h after infection and again after 4 days of infection. Stimulation with TNF-alpha, IFN-gamma, and GM-CSF, but not M-CSF, was associated with mycobacteriostatic and/or mycobactericidal activity in macrophages. Treatment with 10(3) U of TNF-alpha, GM-CSF, and IFN-gamma per ml at 24 h prior to infection with MAC resulted in a significant enhancement in killing of MAC at 4 days after infection, compared with that observed for macrophages exposed to cytokines after infection. When stimulated with lipopolysaccharide or live MAC, intestinal macrophages had produced significantly less TNF-alpha and transforming growth factor beta than had splenic and peritoneal macrophages, although the levels of production of interleukin 6 and interleukin 10 among the three populations of cells were similar. Intestinal macrophages can be stimulated with cytokines to inhibit the intracellular growth of MAC, but they have differentiated abilities to produce cytokines which can modulate the anti-MAC immune response.
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PMID:Response to stimulation with recombinant cytokines and synthesis of cytokines by murine intestinal macrophages infected with the Mycobacterium avium complex. 782 18

In monocytes, the nuclear factor NF-kappa B has been invoked as an important transcription factor in the expression of cytokine genes, of cell-surface receptors and in the expression of human immunodeficiency virus. In such cells, DNA binding activity of NF-kappa B can be detected without intentional stimulation. In our studies, cells of the human monocytic line Mono Mac 6, cultured in medium containing fetal-calf serum and low levels of lipopolysaccharide (LPS), also exhibit such 'constitutive' NF-kappa B, as demonstrated by mobility-shift analysis of nuclear extracts. This nuclear NF-kappa B was still present when contaminant LPS was removed by ultrafiltration and when serum was omitted. Protein-DNA complexes of constitutive NF-kappa B are similar in mobility to the LPS-induced NF-kappa B and both are recognized by an antibody specific to the p50 subunit of NF-kappa B. By contrast, treatment of cells with pyrrolidine dithiocarbamate (PDTC) will only block LPS-induced NF-kappa B, but not the constitutive binding protein. Using LPS-free and serum-free conditions, constitutive NF-kappa B can be detected in different cell lines of the monocytic lineage (HL60, U937, THP-1, Mono Mac 1 and Mono Mac 6), but not in Molt 4 T cells or K562 stem cells. When ordered according to stage of maturation, the amount of constitutive NF-kappa B was not increased in more mature cell lines. Furthermore, when inducing differentiation in Mono Mac 6 cells, with vitamin D3, no change in constitutive or inducible NF-kappa B can be detected. Analysis of primary cells revealed substantial constitutive NF-kappa B-binding activity in blood monocytes, pleural macrophages and alveolar macrophages. The constitutive NF-kappa B appears to be functionally active, since a low level of tumour necrosis factor (TNF) transcript is detectable in monocytes, and this level can be increased by blocking transcript degradation using cycloheximide. The level of constitutive NF-kappa B in these cells is variable and is frequently found to be lower in the more mature macrophages. Constitutive NF-kappa B was not maintained by autocrine action of cytokines TNF, interleukin 6, interleukin 10, granulocyte-macrophage colony-stimulating factor or macrophage colony-stimulating factor, since neutralizing antibodies did not reduce constitutive DNA-binding activity. Furthermore, blockade of prostaglandin or leukotriene biosynthesis did not affect constitutive NF-kappa B.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Constitutive nuclear NF-kappa B in cells of the monocyte lineage. 799 62

In this study we have investigated the effects of interleukin 10 (IL-10) on human peripheral blood eosinophils stimulated with granulocyte/macrophage colony stimulating factor (GM-CSF) and lipopolysaccharide (LPS). We show that LPS was able to enhance eosinophil survival in a dose-dependent manner, as well as release of the cytokines GM-CSF, tumor necrosis factor alpha, and IL-8. LPS-induced eosinophil survival was largely inhibited by an anti-GM-CSF neutralizing antibody and completely blocked by polymyxin B, suggesting GM-CSF involvement in the survival enhancing mechanism and LPS specificity, respectively. IL-10 significantly inhibited survival of, and cytokine production from, eosinophils induced by LPS, but did not inhibit the survival induced by GM-CSF. These observations suggest a novel activation mechanism of eosinophils and, also, that IL-10 may participate in the regulation of diseases characterized by eosinophil infiltration.
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PMID:Interleukin 10 inhibits lipopolysaccharide-induced survival and cytokine production by human peripheral blood eosinophils. 804 46

A cDNA encoding bovine interleukin 10 (IL10) was cloned and sequenced using total cellular RNA derived from concanavalin A (ConA)-stimulated peripheral blood mononuclear cells (PBMC). A cDNA was produced with reverse transcriptase using oligo(dT) primers, and was amplified using primers chosen from consensus regions of the mouse and human IL10 genes. The nucleotide sequence derived from this cDNA shares 84, 79 and 78% homology with the human, mouse and rat cDNAs, respectively. The deduced amino-acid sequence shares an overall 77, 71 and 74% homology with the human, mouse and rat IL10 proteins, respectively. Northern blot analysis of the bovine IL10 mRNA reveals expression of a single 1.8-kb transcript, reaching maximal levels between 8 and 24 h, in ConA-stimulated peripheral T-cells, and weak expression in lipopolysaccharide-activated macrophages.
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PMID:Characterization of a cDNA encoding bovine interleukin 10: kinetics of expression in bovine lymphocytes. 811 15

In this study we have examined the effects of interleukin 10 (IL-10) on polymorphonuclear leukocytes (PMN), and found that it is a potent inhibitor of tumor necrosis factor (TNF), IL-1 beta, and IL-8 secretion triggered by lipopolysaccharide (LPS). Cytokine production by phagocytosing PMN was also inhibited by IL-10, but to a lesser extent than the LPS-induced production. As shown by Northern blot analysis, IL-10 diminished the levels of TNF, IL-1 beta, and IL-8 mRNAs late after the onset of stimulation of PMN with LPS. In addition, we provide evidence that the kinetics of LPS-induced IL-8 production by PMN is composed of two distinct phases. Specifically, our experiments demonstrated that in the first phase, the production of IL-8 is a process directly induced by LPS that lasts for some hours. After this early wave, a second phase begins that is sustained and leads to an elevated production of IL-8 that appears to be due to the endogenous release of TNF and IL-1 beta. This second wave can in fact be blocked by anti-TNF and anti-IL-1 beta neutralizing antibodies, and by IL-10 as the consequence of its downregulatory effects on TNF and IL-1 beta release. Taken together, these findings identify novel biological actions of IL-10 as a suppressor of the inflammatory response.
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PMID:Interleukin 10 (IL-10) inhibits the release of proinflammatory cytokines from human polymorphonuclear leukocytes. Evidence for an autocrine role of tumor necrosis factor and IL-1 beta in mediating the production of IL-8 triggered by lipopolysaccharide. 824 92

This study was designed to define the lipopolysaccharide (LPS) sensitivity of aged mice in terms of lethality and cytokine production and to determine down-regulating responses of corticosterone and interleukin 10 (IL-10). The 50% lethal doses of LPS in young (6- to 7-week-old) and aged (98- to 102-week-old) mice were 601 and 93 microg per mouse (25.6 and 1.6 mg per kg of body weight), respectively. Aged mice were approximately 6.5-fold more sensitive to the lethal toxicity of LPS in micrograms per mouse (16-fold more sensitive in milligrams per kilogram) than young mice. Levels in sera of tumor necrosis factor-alpha (TNF-alpha) IL-1alpha, and IL-6 after intraperitoneal injection of 100 microg of LPS peaked at 1.5, 3, and 3 h, respectively, and declined thereafter in both groups of mice. However, the peak values of these cytokines were significantly higher in aged than in young mice (P < 0.05). Gamma interferon (IFN-gamma) was detectable at 3 h, and sustained high levels were still detected after 12 h in both age groups. Although there were no significant differences in levels of IFN-gamma in sera from both groups, aged mice showed higher IFN-gamma levels throughout the 3- to 12-h study period. Administration of increasing doses of LPS revealed that aged mice had a lower threshold to IL-1alpha production than young mice. In addition, aged mice were approximately 4-fold more sensitive to the lethal toxicity of exogenous TNF in units per mouse (10-fold more sensitive in units per kilogram) than young mice. With regard to down-regulating factors, corticosterone amounts were similar at basal levels and no differences in kinetics after the LPS challenge were observed, whereas IL-10 levels in sera were significantly higher in aged mice at 1.5 and 3 h than in young mice (P < 0.01). These results indicate that aged mice are more sensitive to the lethal toxicities of LPS and TNF than young mice. We conclude that a relatively activated, or primed, state for LPS-induced cytokine production, in spite of full down-regulating responses by corticosterone and IL- 10, may explain at least in part LPS sensitivity in aged mice.
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PMID:Lipopolysaccharide-induced lethality and cytokine production in aged mice. 864 80


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