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)

Interleukin (IL) 12 is a proinflammatory cytokine produced by phagocytic cells, B cells, and other antigen-presenting cells that modulates adaptive immune responses by favoring the generation of T helper type 1 cells. IL-12 mediates some of its physiological activities by acting as a potent inducer of interferon (IFN) gamma production by T and natural killer cells. IFN-gamma enhances the ability of the phagocytic cells to produce IL-12 and other proinflammatory cytokines. Thus, IL-12-induced IFN-gamma acts in a positive feedback loop that represents an important amplifying mechanism in the inflammatory response to infections. We show here that IFN-gamma enhances IL-12 production mostly by priming phagocytic cells for lipopolysaccharide (LPS)-induced transcription of the IL-12 p40 gene, which encodes the heavy chain of the IL-12 heterodimer; furthermore, IFN-gamma directly induces transcription of the IL-12 p35 gene, which encodes the light chain of IL-12, and has at least an additive effect with LPS stimulation in inducing its transcription. The priming effect of IFN-gamma on the LPS-induced p40 gene transcription requires preincubation of the cells with IFN-gamma for at least 8 h to obtain a maximal effect. The priming effect of IFN-gamma for IL-12 production is predominantly at the transcriptional level for both the p40 and the p35 gene, and no evidence for a major role of posttranscriptional or translational mechanisms was found. A 3.3-kb human IL-12 p40 promoter construct transfected into cell lines recapitulated the tissue specificity of the endogenous gene, being silent in two human T cell lines, constitutively active in two human Epstein-Barr virus-positive B lymphoblastoid cell lines, and LPS inducible in the human THP-1 and mouse RAW264.7 monocytic cell lines. Because the RAW264.7 cell line is easily transfectable and regulates the endogenous IL-12 p40 gene in response to IFN-gamma or LPS similarly to human monocytes, it was used for analysis of the regulation of the cloned human IL-12 p40 promoter. A requirement for the region between -222 and -204 in both LPS responsiveness and IFN-gamma priming was established. This region contains an ets consensus sequence that was shown to mediate activation of the promoter by IFN-gamma and LPS, as well as by a cotransfected ets-2. The -222 construct was also regulated in a tissue-specific manner. Two other elements, IRF-1 located at -730 to -719, and NF-IL6 at -520 to -512, were also studied by deletion analysis, which did not result in decreased response to IFN-gamma and LPS stimulation.
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PMID:The interleukin 12 p40 gene promoter is primed by interferon gamma in monocytic cells. 855 Dec 18

Since glucocorticoid effects on inflammatory processes may be mediated via modulation of cytokine release, different types of myelomonocytic cells were stimulated in vitro with lipopolysaccharide (50 ng/ml) or phorbol myristate acetate (25 ng/ml) plus the ionophore A23187, 2 x 10(-7) M, and release of interleukin (IL)-1 beta, IL-8 and tumor necrosis factor (TNF)-alpha was measured after 24 h by ELISA. Peripheral blood mononuclear cells from two allergic and two normal human donors released similarly large quantities of IL-8 and lower amounts of IL-1 beta and TNF-alpha. This also held for myelomonocytic cell lines, with THP-1 cells being most active, followed by U-937 and HL-60 cells. All potent glucocorticoids studied caused a dose-dependent inhibition of cytokine release from donor cells, being most marked for IL-1 beta and lowest for IL-8. Inhibition of cytokine release was also noted with U-937 cells, with clear differences in potency between the glucocorticoids, whereas release was enhanced in all experiments with THP-1 cells. These results were confirmed with Northern blot analysis. Modulating effects of glucocorticoids on cytokine release are thus complex, and are particularly dependent on the cell type studied.
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PMID:Glucocorticoid-induced modulation of cytokine secretion from normal and leukemic human myelomonocytic cells. 856 84

We recently reported that cyclic AMP (cAMP) specifically inhibits lipopolysaccharide (LPS)-induced interleukin 1 beta (IL-1 beta) transcription initiation in astrocytic cells but enhances the LPS induction of IL-1 beta in monocytic cells. The purpose of this study was to determine how cAMP differentially regulates LPS-induced IL-1 beta transcription in these two cell types. Two essential components of the mitogen-activated protein (MAP) kinase signal-transduction pathway, extracellular-signal-regulated kinase (ERK2; p41 mapk) and Raf-1, have been shown to be targets of LPS stimulation in other cell types, and therefore may be linked to the regulation of IL-1 beta transcription. In the human astrocytic cell line, U-373MG, LPS was found to strongly activate (and cAMP to inhibit) both ERK2 and Raf-1. In the human monocytic cell line, THP-1, LPS minimally activated ERK2 and did not activate Raf-1. These findings suggest that, in astrocytic cells, elevated intracellular cAMP levels may negatively regulate LPS activation of IL-1 beta via the MAP kinase signalling pathway. In contrast, this pathway is not significantly activated by LPS in monocytic cells, thus inhibition by elevated intracellular cAMP levels would not affect IL-1 beta transcription.
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PMID:Differential induction of the mitogen-activated protein kinase pathway by bacterial lipopolysaccharide in cultured monocytes and astrocytes. 857 86

alpha-Melanocyte-stimulating hormone (alpha-MSH), a tridecapeptide derived from pro-opiomelanocortin, has potent antiinflammatory activity in laboratory animals. alpha-MSH inhibits nitric oxide production by murine macrophages, an influence believed to reflect activation of an autocrine circuit in these cells, one that is based on production and release of alpha-MSH and subsequent stimulation of melanocortin receptors. We found that THP-1 cells, human monocytic cells, produced alpha-MSH; this production was increased by interleukin-6, tumor necrosis factor a, or concanavalin A. These cells also expressed the gene for the human alpha-MSH receptor MC1. Unlike murine macrophages, THP-1 cells produced little nitrite in response to interferon-gamma (IFN-gamma) and lipopolysaccharide, and a-MSH inhibited this production only slightly. However, production of neopterin, a presumed primate homologue of nitric oxide in lower animals, was increased in THP-1 cells stimulated with INF-gamma plus TNF-alpha and alpha-MSH significantly inhibited this production. The evidence indicates that an autocrine regulatory circuit based on alpha-MSH occurs in human monocyte/macrophages much as in murine macrophages. alpha-MSH-induced modulation of specific inflammatory mediators/cytotoxic agents appears to differ depending on the importance of the mediators in the myelomonocytic cells of different species.
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PMID:alpha-MSH production, receptors, and influence on neopterin in a human monocyte/macrophage cell line. 860 97

This study examined the effects of endogenous urokinase (uPA) on lipopolysaccharide (LPS)-stimulated tumor necrosis factor alpha (TNF-alpha) secretion in THP-1 mononuclear phagocytes. Anti-uPA monoclonal antibody (mAb) suppressed LPS-driven TNF-alpha secretion by 61.6 +/- 5.9% (P<.001), and PAI-1, a uPA inhibitor, suppressed it to 53.1 +/- 8.2% of the control value (P<.001). Up-regulation of TNF-alpha mRNA was suppressed in parallel with secreted TNF-alpha protein. TNF-alpha secretion was unaffected by depleting plasminogen or by aprotinin, a plasmin inhibitor. When endogenous uPA was displaced from the cell, exogenous high-molecular-weight (intact) uPA augmented LPS-driven TNF-alpha secretion. By contrast, a uPA fragment containing the catalytic domain was inhibitory, and the uPA receptor-binding domain had no effect. We conclude that endogenous uPA amplifies TNF-alpha neosynthesis of LPS-stimulated THP-1 mononuclear phagocytes. The effect requires intact uPA and is independent of plasmin activity. This represents a novel mechanism by which a mononuclear phagocyte-derived protease contributes to generating proinflammatory signals.
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PMID:Endogenously produced urokinase amplifies tumor necrosis factor-alpha secretion by THP-1 mononuclear phagocytes. 860 4

Activation of macrophages by bacterial lipopolysaccharide (LPS) induces transcription of genes that encode for proinflammatory regulators of the immune response. Previous work has suggested that activation of the transcription factor activator protein 1 (AP-1) is one LPS-induced event that mediates this response. Consistent with this notion, we found that LPS stimulated AP-1-mediated transcription of a transfected reporter gene in the murine macrophage cell line RAW 264.7. As AP-1 activity is regulated in part by activation of the c-Jun N-terminal kinase (JNK), which phosphorylates and subsequently increases the transcriptional activity of c-Jun, we examined whether LPS treatment of macrophages resulted in activation of this kinase. LPS treatment of RAW 264.7 cells, murine bone marrow-derived macrophages, and the human monocyte cell line THP-1 resulted in rapid activation of the p46 and p54 isoforms of JNK. Treatment with wild-type and rough mutant forms of LPS and synthetic lipid A resulted in JNK activation, while pretreatment with the tyrosine kinase inhibitor herbimycin A inhibited this response. Binding of LPS-LPS binding protein (LBP) complexes to CD14, a surface receptor that mediates many LPS responses, was found to be crucial, as pretreatment of THP-1 cells with the monoclonal antibody 60b, which blocks this binding, inhibited JNK activation. These results suggest that LPS activation of JNK in monocyte/macrophage cells is a CD14- and protein tyrosine phosphorylation-dependent event that may mediate the early activation of AP-1 in regulating LPS-triggered gene induction.
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PMID:Activation of c-Jun N-terminal kinase in bacterial lipopolysaccharide-stimulated macrophages. 861 Jan 16

The production of gelatinase B by macrophages is relevant in the immunological and migratory functions of macrophages. CGP 41251, an inhibitor of protein kinase C (PKC), was found to stimulate the expression of gelatinase B in macrophages, as shown by the study of two different monocytic/macrophagic cell lines, mouse RAW 264.7 and human THP-1 cells. When human monocytes and rat peritoneal macrophages were treated with CGP 41251, insignificant increases of 10 and 25% were obtained. This can possibly be due to the presence of contaminating cells in these two enriched populations, since the CGP 41251 treatment of non-macrophagic cell lines inhibited their PMA-induced gelatinase B production. Taken together, these results suggest that the stimulatory effect of CGP 41251 is specific to cells of the monocytic lineage. Using RAW 264.7 cells as a model, the effect of CGP 41251 is additive to that obtained using lipopolysaccharide (LPS) and phorbol 12-myristate 13-acetate (PMA), as revealed by gelatin zymography and Northern blot analysis. The stimulatory effect of CGP 41251 on gelatinase B production in RAW 264.7 was: (a) inhibited by calphostin C (as is the LPS-induced response), indicating a PKC-dependence; (b) inhibited by dexamethasone (as opposed to the LPS-induced response); and (c) enhanced by addition of trans-retinoic acid (RA). In fact, RA can induce gelatinase B production, either alone or in synergy with LPS and/or CGP 41251, since the combination of the three agents gives the highest gelatinase B response, at both the protein and the mRNA levels. This represents an important observation considering the RA is now being tested as an anti-cancer agent and proposed for prevention studies.
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PMID:Synergistic and selective stimulation of gelatinase B production in macrophages by lipopolysaccharide, trans-retinoic acid and CGP 41251, a protein kinase C regulator. 861 33

These studies examine the molecular basis for increased transcription of tissue factor (TF) in THP-1 cells stimulated with lipopolysaccharide (LPS). DNase I footprinting identified six sites of protein-DNA interaction between -383 and the cap site that varied between control and induced extracts. Four footprints show qualitative differences in nuclease sensitivity. Footprints I (-85 to -52) and V (-197 to -175) are induction-specific and localize to regions of the promoter that mediate serum, phorbol ester, partial LPS response (-111 to +14), and the major LPS-inducible element (-231 to -172). Electrophoretic mobility shift assays with the -231 to -172 probe demonstrate JunD and Fos binding in both control and induced nuclear extracts; however, binding of c-Jun is only detected following LPS stimulation. Antibody inhibition studies implicate binding of Ets-1 or Ets-2 to the consensus site between -192 and -177, a region that contains an induction-specific footprint. The proximal region (-85 to -52), containing the second inducible footprint, binds Egr-1 following induction. These data suggest that LPS stimulation of THP-1 cells activates binding of c-Jun, Ets, and Egr-1 to the TF promoter and implicates these factors in the transcriptional activation of TF mRNA synthesis.
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PMID:Lipopolysaccharide induction of THP-1 cells activates binding of c-Jun, Ets, and Egr-1 to the tissue factor promoter. 864 47

Interleukin 12 (IL-12) strongly augments gamma interferon production by natural killer (NK) and T cells. IL-12 also promotes effective cell-mediated immune responses, which are particularly important against intracellular bacteria such as Listeria monocytogenes. While the lipopolysaccharide (LPS) of gram-negative bacteria induces monocyte production of IL-12, the relevant gram-positive components which induce IL-12 production are uncharacterized. We used the human monocytic cell line THP-1 to study IL-12 induction by gram-positive bacteria. Muramyl dipeptides as well as the major muramyl tetrapeptide component of Streptococcus pneumoniae were inactive for inducing IL-12. In contrast, lipoteichoic acid (LTA), a predominant surface glycolipid of gram-positive bacteria, potently induced IL-12 p40 gene expression. A competitive LPS antagonist, Rhodobacter sphaeroides LPS, inhibited LTA-induced IL-12 production, suggesting a common pathway for LPS and LTA in IL-12 activation. Pretreatment of cells with anti-CD14 monoclonal antibody blocked both LPS and LTA induction of IL-12 p40 expression. LTA also induced Thl development in naive CD4 T cells by an IL-12-dependent mechanism, indicating direct induction of physiologic levels of IL-12. Together, these results show that LTA is a potent surface structure of gram-positive bacteria which induces IL-12 in monocytes through a CD14-mediated pathway.
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PMID:Lipoteichoic acid preparations of gram-positive bacteria induce interleukin-12 through a CD14-dependent pathway. 867 86

The effect if thalidomide on tumor necrosis factor alpha (TNF-alpha) produced in vitro by lipopolysaccharide (LPS) stimulated human cells was investigated. In cultures of LPS stimulated human mononuclear cells enriched for adherent cells and in cultures of LPS stimulated human monocytes of the cell line-THP-1, thalidomide enhanced the synthesis of TNF-alpha. When cultures of unfractionated peripheral blood mononuclear cells were stimulated with LPS, thalidomide decreased the synthesis of TNF-alpha. Depending on the type of cells stimulated with LPS in vitro, thalidomide, at concentrations achieved in vivo, can either enhance or suppress the synthesis of TNF-alpha.
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PMID:Thalidomide can be either agonistic or antagonistic to LPS evoked synthesis of TNF-alpha by mononuclear cells. 868 39


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