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)

In macrophages, nuclear factor kappa B (NF-kappa B) has been shown to transactivate the promoters of many cytokines, including tumor necrosis factor-alpha (TNF-alpha). We have used the -510 kappa B binding site from the murine TNF-alpha promoter to assay the induction of NF-kappa B in murine macrophages by various stimuli. A basal level of NF-kappa B activity in murine macrophages was detectable, and this activity was enhanced by treatment of these cells with lipopolysaccharide (LPS) or interleukin-2 (IL-2). Interferon-gamma (IFN-gamma), an important regulator of macrophage gene expression, significantly enhanced NF-kappa B activity and altered the apparent molecular weight of the NF-kappa B1-like proteins in LPS-stimulated and IL-2-stimulated murine macrophages. The NRD (NF-kappa B/Rel/Dorsal) complexes induced by LPS and IFN-gamma were further characterized by addition of antisera to electrophoretic mobility shift assay (EMSA) reaction mixtures. NF-kappa B1/p50 was a component of all complexes, whereas RelA/p65 was present in the IFN-gamma/LPS-stimulated activity. IFN-gamma priming or treatment with LPS for 19 h resulted in an upregulation of the larger species of NF-kappa B1/p50. In addition, regulation of the two pools of NF-kappa B1/p50 by IFN-gamma was confirmed by Western immunoblot analysis of cytosolic and nuclear extracts. This is the first demonstration of the presence of two pools of NF-kappa B1/p50 differentially regulated in response to cytokine activation of macrophages.
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PMID:Two forms of NF-kappa B1 (p105/p50) in murine macrophages: differential regulation by lipopolysaccharide, interleukin-2, and interferon-gamma. 918 68

Interferon-gamma (IFN-gamma) and transforming growth factor-beta (TGF-beta) are known to be a potent inducer and inhibitor for macrophage (Mo) activation process, respectively. In the present study we established that the nucleated erythroid cells (NEC) separated from the spleens of adult (CBA x C57BL/6)F1 (CBF, H-2k/H-2d) mice following phenylhydrazine treatment are potentially capable of inducing nitric oxide (NO) production in thioglycollate broth-elicited peritoneal macrophages (Mo). The stimulating effect of both NEC and their culture supernatant on NO secretion by Mo was most apparent in the presence of bacterial lipopolysaccharide (LPS) and neutralizing antibodies (Abs) to TGF-beta and was largely reversed by the addition to the culture of neutralizing Abs to IFN-gamma. Collectively these results suggest that NEC, through production of IFN-gamma and TGF-beta, may exert a regulatory influence on development and functionality of cells pertaining to monocyte (Mc)/Mo lineage.
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PMID:A role for interferon-gamma and transforming growth factor-beta in erythroid cell-mediated regulation of nitric oxide production in macrophages. 920 73

Interferon-gamma (IFN-gamma) upregulates expression of certain genes in monocytes, including cell-surface molecules such as HLA class II, B7, and ICAM-1. IFN-gamma also potentiates production of cytokines such as tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta) and IL-12. Conversely, IL-10 downregulates expression of many of these same genes and often antagonizes the effects of IFN-gamma. IL-10 is known to inhibit TNF-alpha production in lipopolysaccharide (LPS)-stimulated monocytes; however, the effects of IL-10 on TNF receptor (TNF-R) expression are not well defined. We examined the effects of IL-10 on production of both membrane-associated (m) and soluble (s) TNF-R type II (sTNF-RII) by purified human CD14(+) monocytes. We also compared the effects of IFN-gamma and IL-10 on production of TNF-alpha and sTNF-RII by these cells. Monocytes constitutively expressed low levels of TNF-RII mRNA and mTNF-RII protein. LPS stimulation induced rapid, but transient loss (shedding) of mTNF-RII molecules and a delayed, but marked increase in TNF-RII mRNA levels. IL-10 increased expression of both mTNF-RII and sTNF-RII by LPS-stimulated monocytes, whereas IFN-gamma decreased their expression. The increased levels of sTNF-RII in cultures of IL-10-treated monocytes correlated directly with increased levels of TNF-RII mRNA and inversely with the levels of TNF-alpha mRNA. The ability of IL-10 to upregulate TNF-RII gene expression was transcriptionally mediated because actinomycin D blocked this effect. Furthermore, IL-10 treatment did not alter the half-life of TNF-RII mRNA transcripts in LPS-stimulated monocytes. To further examine the mechanism by which IL-10 potentiates TNF-RII gene expression, a 1.8-kb fragment of the human TNF-RII promoter cloned into a luciferase expression vector (pGL2-basic) was transfected into the IL-10-responsive macrophage cell line, RAW264.7. Although IL-10 alone induced only minimal promoter activity in these cells, it markedly increased the LPS-induced response, providing further evidence that the ability of IL-10 to amplify TNF-RII gene expression is transcriptionally controlled. Together, these findings demonstrate that IL-10 coordinately downregulates expression of TNF-alpha and upregulates expression of TNF-RII, particularly the soluble form of this receptor, in monocytes.
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PMID:Interleukin-10 upregulates tumor necrosis factor receptor type-II (p75) gene expression in endotoxin-stimulated human monocytes. 935 87

We have established a cell line cloned from primary-cultured microglia obtained from p53-deficient mice. The cell line, MG5, could be grown in astrocyte-conditioned medium and has been maintained for more than a year. MG5 cells are immunocytochemically positive for Mac-1 and F4/80 antibody and express the major histocompatibility complex (MHC) class I antigen, leukocyte function-associated antigen-1, leukocyte common antigen, and intercellular adhesion molecular-1 mRNA. Interferon-gamma enhanced the expression of MHC class II antigen mRNA in MG5 cells. We previously identified a novel calcium-binding protein, Iba1 (ionized calcium-binding adapter molecule 1), which is highly and specifically expressed in cultured microglia. Iba1 protein was also immunocytochemically demonstrated in MG5 cells. The cells retained non-specific esterase activity, 5'-nucleotidase activity, acid phosphatase activity, and phagocytic ability. Like primary cultured microglia from wild-type mice, MG5 cells released nitric oxide in response to lipopolysaccharide, and actively proliferated in the presence of mitogenic factors such as macrophage-colony stimulating factor (M-CSF), granulocyte/macrophage-CSF (GM-CSF), and interleukin-3 (IL-3). Tyrosine-phosphorylation of M-CSF receptor in MG5 cells was induced by the addition of M-CSF or astrocyte-conditioned medium. These findings indicate that MG5 cells preserve the morphological, biochemical, and physiological properties of primary-cultured microglia well. The MG5 cell line will be a useful tool for studying microglial function.
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PMID:Generation and characterization of a microglial cell line, MG5, derived from a p53-deficient mouse. 938 38

Chemokines play an important role in the regulation of endothelial cell (EC) function, including proliferation, migration and differentiation during angiogenesis, and re-endothelialization after injury. In this study, reverse transcriptase-polymerase chain reaction was used to reveal expression of various CXC and CC chemokine receptors in human umbilical vein EC. Northern analysis showed that CXCR4 was selectively expressed in vascular EC, but not in smooth muscle cells. Compared with other chemokines, stromal cell-derived factor-1alpha (SDF-1alpha), the known CXCR4 ligand, was an efficacious chemoattractant for EC, causing the migration of approximately 40% input cells with an EC50 of 10-20 nM. Of the chemokines tested, only SDF-1alpha induced a rapid, though variable mobilization of intracellular Ca2+ in EC. Experiments with actinomycin D demonstrated that CXCR4 transcripts were short-lived, indicating a rapid mRNA turnover. Interferon-gamma (IFN-gamma) caused a pronounced down-regulation of CXCR4 mRNA in a concentration- and time-dependent manner. In a striking functional correlation, IFN-gamma treatment also attenuated the chemotactic response of EC to SDF-1alpha. IL-1beta, tumor necrosis factor-alpha, and lipopolysaccharide produced a time course-dependent biphasic effect on CXCR4 transcription. Expression of CXCR4 in EC is significant, more so as it and several CC chemokine receptors have been shown to serve as fusion co-receptors along with CD4 during human immunodeficiency virus infection. Taken together, these findings provide evidence of chemokine receptor expression in EC and offer an explanation for the action of chemokines like SDF-1alpha on the vascular endothelium.
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PMID:Chemokine receptors in human endothelial cells. Functional expression of CXCR4 and its transcriptional regulation by inflammatory cytokines. 946 27

Most patients with primary IgA nephropathy (IgAN) have a significantly higher memory repertoire of IgA1-producing B lymphocytes in their bone marrow together with high plasma levels of IgA1. The connection between the mucosal immune system and the bone marrow compartment is probably based on traffic of either antigen-presenting cells (APC) or antigen-specific lymphocytes. Cytokines play an important role in the proliferation and differentiation of lymphoid cells. In order to mimic the in vivo situation as much as possible, we assessed cytokine production profiles ex vivo in 23 IgAN patients and matched controls, using lipopolysaccharide (LPS)- or phytohaemagglutinin (PHA)-stimulated whole blood (WB) cultures. Interferon-gamma (IFN-gamma), IL-2, IL-6, IL-10 and tumour necrosis factor-alpha (TNF-alpha) production in culture supernatants were determined by cytokine-specific ELISAs. Compared with controls, PHA-stimulated cultures resulted in significantly higher IL-10 (P<0.001), IL-2 (P<0.005) and IFN-gamma (P<0.001) levels in IgAN patients, but no significant differences in TNF-alpha or IL-6 levels were found. In LPS-stimulated cultures, the only significant difference (P<0.001) between the two groups was the increased IL-10 production in IgAN patients. The enhanced cytokine production in stimulated WB cultures suggests altered monocyte-related T cell responses in patients with IgAN. Increased IL-10 production may eventually result in an increased number of IgA-producing B lymphocytes in the bone marrow. In addition, high levels of endogenous IL-10 may down-regulate the effector functions of monocytes, or possibly APC in general, and consequently the IgA response at the mucosal level.
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PMID:Increased IL-10 production by stimulated whole blood cultures in primary IgA nephropathy. 948 15

Adrenomedullin (AM) is a potent vasorelaxant peptide recently identified in extracts of pheochromocytoma. We have found that AM is actively secreted from endothelial cell (EC) and vascular smooth muscle cell (VSMC). To elucidate the function of AM secreted from EC, the effects of 43 substances on secretion of AM from cultured rat EC were examined in this study. We first confirmed that synthesized AM was not stored but constitutively secreted from EC, indicating that the amount secreted could be used as an index of AM synthesis in EC. EC secreted AM at a rate 5.8 times higher than VSMC, and AM gene transcription in EC significantly contributed to the total aortic AM messenger RNA. Tumor necrosis factor, interleukin-1, and lipopolysaccharide augmented AM secretion from EC, showing cooperative effects, which suggests that AM secreted from EC participates in the induction of hypotension in septic shock. Transforming growth factor beta1 and FCS suppressed AM secretion but stimulated endothelin-1 (ET-1) secretion. Thrombin potently stimulated AM secretion from EC but suppressed it from VSMC. Thyroid hormone and phorbol ester increased AM and ET-1 secretion but to a lesser extent. Interferon-gamma inhibited AM secretion from EC, whereas oxidized LDL stimulated it. Regulation of AM production in EC is found to be similar to that of VSMC with several exceptions, but AM and ET-1 production in EC are deduced to be controlled independently and by different mechanisms. AM stimulates cAMP production in EC, though receptors expressed on cultured rat EC are not specific to AM but to calcitonin gene-related peptide. Based on these findings, AM production in EC is thought to be regulated by a variety of substances coming from blood and neighboring cells, and the secreted AM is deduced to dilate blood vessels as an endothelium-derived relaxing factor competing with ET-1.
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PMID:Regulation of adrenomedullin production in rat endothelial cells. 949 11

Interferon-gamma (IFN-gamma)-induced, indoleamine dioxygenase-catalyzed tryptophan catabolism was studied in cultured human foreskin fibroblasts using the increase in cellular kynurenine synthesis as an index of gene expression. The time courses of the inhibition of IFN-gamma-induced kynurenine synthesis by actinomycin D and cycloheximide showed that the indoleamine dioxygenase gene was transcribed as early as 2 h and translated as early as 5 h after initiation of IFN treatment. Expression was completely inhibited by the Ser/Thr kinase inhibitor, H-7 (66 microM), during the first 2 h after IFN-gamma treatment. Prolonged pretreatment of cells with high concentrations of staurosporine (380 nM) or genestein (610 microM) inhibited expression by 38% and 53%, respectively. Genestein also inhibited expression when it was added to cultures between 8 and 24 h after IFN-gamma treatment. The expression of kynurenine synthesis was inhibited by A23817 during the first 4 h after IFN treatment by mechanisms that were independent of cyclooxygenase, calmodulin, and calcineurin. Exogenous gangliosides (bovine brain gangliosides and purified GM1) inhibited IDO expression throughout the first 24 h after IFN-gamma treatment by mechanisms that did not involve effects on Ca2+ channels. Other biologic response modifiers, including phorbol myristic acetate, arachidonic acid, lipopolysaccharide, analogs of cAMP and cGMP, W-7, and sphingosine, did not induce IDO in the absence of IFN-gamma, nor did they modulate IFN-gamma-induced expression. These results indicate that the expression of kynurenine synthesis is modulated at the transcriptional and posttranscriptional levels by protein tyrosine kinase and by a Ser/Thr kinase with properties distinctly different from those of conventional protein kinase C. The capacity for attenuation of this IFN-gamma-induced response over its entire time course by many effectors and through multiple cellular signaling pathways may represent a mechanism for fine-tuning the level of oxidative tryptophan metabolism to meet the needs of a particular cytostatic or antiproliferative response.
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PMID:Expression and regulation of interferon-gamma-induced tryptophan catabolism in cultured skin fibroblasts. 971 67

Inhaled nitric oxide is a selective pulmonary vasodilator used for the treatment of pulmonary hypertension. The potential adverse effects of inhaled nitric oxide are unknown and represent the focus of the present studies. Whereas inhalation of nitric oxide (10 to 100 ppm, 5 h) by Balb/c mice had no effect on the number or type of cells recovered from the lung, a dose-related increase in bronchoalveolar lavage protein was observed, suggesting that nitric oxide induces alveolar epithelial injury. To determine if this was associated with altered alveolar macrophage activity, we quantified production of reactive oxygen and nitrogen intermediates by these cells. Interferon-gamma, alone or in combination with lipopolysaccharide (LPS), induced expression of inducible nitric oxide synthase (iNOS) protein and nitric oxide production by alveolar macrophages. Cells from mice exposed to 20 to 100 ppm nitric oxide produced significantly more nitric oxide and expressed greater quantities of iNOS than cells from control animals. Superoxide anion production and peroxynitrite generation by alveolar macrophages were also increased after exposure of mice to nitric oxide. This was correlated with increased antinitrotyrosine antibody binding to macrophages in histologic sections. Taken together, these data demonstrate that inhaled nitric oxide primes lung macrophages to release reactive oxygen and nitrogen intermediates. Increased production of these mediators by macrophages following inhalation of nitric oxide may contribute to tissue injury.
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PMID:Inhaled nitric oxide primes lung macrophages to produce reactive oxygen and nitrogen intermediates. 973 Oct 28

The mechanisms whereby trypanotolerant N'Dama cattle control infection with Trypanosoma congolense are unknown. Previous studies have suggested that the monocytes of N'Dama cattle are more highly activated during infection than those of trypanosusceptible Boran cattle. However, we have recently reported that the monocytes of Boran cattle have a reduced capacity to secrete nitric oxide during trypanosome infection. We therefore evaluated the production of nitric oxide by monocytes of trypanotolerant N'Dama cattle infected with T. congolense in response to interferon-gamma, bacterial lipopolysaccharide or trypanosome antigens. Interferon-gamma-induced nitric oxide production was decreased between days 25 and 76 of infection, while lipopolysaccharide-induced secretion of nitric oxide was increased at days 13 and again at day 76 post-infection. Trypanosome antigens did not elicit nitric oxide production. Analysis of interleukin-10 mRNA transcription in peripheral blood leucocytes revealed an increase at time points that coincided with decreased interferon-gamma-induced nitric oxide synthesis. In contrast, interferon-gamma mRNA expression was not changed during infection while tumour necrosis factor-alpha was slightly reduced at day 32 post-infection. Recombinant interleukin-10 suppressed interferon-gamma-induced nitric oxide and tumour necrosis factor-alpha secretion, but not lipopolysaccharide-induced nitric oxide secretion in cultures of peripheral blood mononuclear cells and monocytes of uninfected cattle. These results suggest that the nitric oxide response of monocytes to IFN-gamma but not lipopolysaccharide, is suppressed during infection. The kinetics of the upregulation of interleukin-10 and its biological activity indicate a possible association with the depression of nitric oxide production and control of tumour necrosis factor-alpha.
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PMID:Trypanosoma congolense infection of trypanotolerant N'Dama (Bos taurus) cattle is associated with decreased secretion of nitric oxide by interferon-gamma-activated monocytes and increased transcription of interleukin-10. 976 9


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