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)

This paper deals with the CBA/N mice, a strain bearing a genetic defect in their B-cell compartment. By using a previously described system we have been able to show that the immature cells of CBA/N mice are functionally indistinguishable from normal immature cells, in that both can be triggered to respond to thymus-independent (TI) antigens, provided they are supplied with helper T cells. When the maturation is completed, CBA/N B cells are unable to respond to TI antigens (like lipopolysaccharide and polyvinyl pyrrolidine) irrespective of the presence of helper T cells, whereas normal mature B cells have grown able to respond without any help. These data allow us to reject the hypothesis that CBA/N mice are arrested at an immature stage and clearly support the idea that they have deviated during development so that only thymus-dependent B cells develop.
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PMID:Ontogeny of B cells in CBA/N mice. Evidence for a stage of responsiveness to thymus-independent antigens during development. 31 89

Dithiocarbamates and iron chelators were recently considered for the treatment of AIDS and neurodegenerative diseases. In this study, we show that dithiocarbamates and metal chelators can potently block the activation of nuclear factor kappa B (NF-kappa B), a transcription factor involved in human immunodeficiency virus type 1 (HIV-1) expression, signaling, and immediate early gene activation during inflammatory processes. Using cell cultures, the pyrrolidine derivative of dithiocarbamate (PDTC) was investigated in detail. Micromolar amounts of PDTC reversibly suppressed the release of the inhibitory subunit I kappa B from the latent cytoplasmic form of NF-kappa B in cells treated with phorbol ester, interleukin 1, and tumor necrosis factor alpha. Other DNA binding activities and the induction of AP-1 by phorbol ester were not affected. The antioxidant PDTC also blocked the activation of NF-kappa B by bacterial lipopolysaccharide (LPS), suggesting a role of oxygen radicals in the intracellular signaling of LPS. This idea was supported by demonstrating that treatment of pre-B and B cells with LPS induced the production of O2- and H2O2. PDTC prevented specifically the kappa B-dependent transactivation of reporter genes under the control of the HIV-1 long terminal repeat and simian virus 40 enhancer. The results from this study lend further support to the idea that oxygen radicals play an important role in the activation of NF-kappa B and HIV-1.
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PMID:Dithiocarbamates as potent inhibitors of nuclear factor kappa B activation in intact cells. 131 83

Classically, osteoarthritis (OA) has been considered a noninflammatory disease. However, the detection of selected inflammatory mediators in osteoarthritic fluid, in the absence of significant inflammatory cell infiltrate, is increasingly appreciated. We sought to identify the inflammatory component in human OA-affected cartilage that may be involved in cartilage damage/destruction. Using Western blot analysis and an antibody to the conserved region of nitric oxide synthase (NOS), we have observed up-regulation of NOS, one of the "key players" of inflammation, in chondrocytes of OA-affected patients. Remarkably, none of the cartilage samples examined from normal joints demonstrated detectable amounts of this NOS. Western blot analysis using the same alpha-NOS antibody indicated that this NOS from OA-affected cartilage (OA-NOS) was larger in size than (and distinct from) transfected human hepatocyte or murine inducible NOS (iNOS) (150 versus 133 kD) and similar in size to neuronal constitutive NOS (ncNOS). Antibodies specific for iNOS showed binding to murine and human iNOS but not to OA-NOS, endothelial constitutive NOS, or ncNOS. Antibodies specific for ncNOS bound to ncNOS and also to OA-NOS, but not to murine or human iNOS or endothelial constitutive NOS. Incubation of OA cartilage in serum-free medium resulted in spontaneous release, for up to 72 h, of substantial amounts of nitrite (up to approximately 80 microM/100 mg wet tissue), which could be inhibited by at least 80% with various inhibitors of iNOS, including inhibitors of protein synthesis and transcription factor NF-kappa B, but which (unlike murine macrophage iNOS) was not sensitive to hydrocortisone or TGF-beta. Exposure of OA-affected cartilage to interleukin 1 beta, tumor necrosis factor-alpha, and lipopolysaccharide resulted in approximately 20-50% augmentation of nitrite accumulation, which was also sensitive to cycloheximide and pyrrolidine dithiocarbamate. Hence, our data indicate that OA-NOS (based on immunoreactivity and molecular weight) is similar to ncNOS and that it releases nitric oxide, which may contribute to the inflammation and pathogenesis of cartilage destruction in OA.
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PMID:The expression and regulation of nitric oxide synthase in human osteoarthritis-affected chondrocytes: evidence for up-regulated neuronal nitric oxide synthase. 750 55

The effects of cytokines, lipopolysaccharide (LPS), 8-bromoadenosine 3',5'-cyclic monophosphate (8-BrcAMP), and pyrrolidine dithiocarbamate (PDTC), an inhibitor of nuclear factor kappa B (NF-kappa B) activation, on inducible nitric oxide synthase (iNOS) expression were studied in the medullary thick ascending limb of Henle's loop cell line ST-1. LPS + interferon-gamma (IF-gamma) promoted a time-dependent increase in nitrite (a NO metabolite) and iNOS mRNA and the appearance of NF-kappa B p50 and p65 in nuclear protein extracts. Actinomycin D but not cycloheximide prevented the LPS + IF-gamma induction of iNOS mRNA and NO synthesis, indicating that iNOS transcriptional activation by LPS + IF-gamma does not require newly synthesized proteins. PDTC inhibited the LPS + IF-gamma induction of NO, iNOS mRNA, and the appearance of NF-kappa B in nuclear protein extracts, suggesting that NF-kappa B mobilization and trans-activation of the iNOS gene mediates this induction. In contrast to other cell types, cycloheximide did not alter iNOS mRNA stability, and 8-BrcAMP did not alter basal or LPS+IF-gamma induced NO production in ST-1 cells.
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PMID:Role of NF-kappa B in the regulation of inducible nitric oxide synthase in an MTAL cell line. 750 39

The promoter of the murine gene encoding inducible nitric oxide synthase (iNOS) contains an NF-kappa B site beginning 55 base pairs upstream of the TATA box, designated NF-kappa Bd. Reporter constructs containing truncated promoter regions, when transfected into macrophages, revealed that NF-kappa Bd is necessary to confer inducibility by bacterial lipopolysaccharide (LPS). Oligonucleotide probes containing NF-kappa Bd plus the downstream 9 or 47 base pairs bound proteins that rapidly appeared in the nuclei of LPS-treated macrophages. The nuclear proteins bound to both probes in an NF-kappa Bd-dependent manner, but binding was resistant to cycloheximide only for the shorter probe. The proteins binding both probes reacted with antibodies against p50 and c-rel but not RelB; those binding the shorter probe also reacted with anti-RelA (p65). Pyrrolidine dithiocarbamate, which acts as a specific inhibitor of NF-kappa B, blocked both the activation of the NF-kappa Bd-binding proteins and the production of NO in LPS-treated macrophages. Thus, activation of NF-kappa B/Rel is critical in the induction of iNOS by LPS. However, additional, newly synthesized proteins contribute to the NF-kappa Bd-dependent transcription factor complex on the iNOS promoter in LPS-treated mouse macrophages.
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PMID:Role of transcription factor NF-kappa B/Rel in induction of nitric oxide synthase. 750 26

We previously demonstrated that lipopolysaccharide (LPS) increases expression of the prostaglandin H synthase-2 (PGHS-2) gene (Hempel, S.L., Monick, M.M., and Hunninghake, G.W. (1994) J. Clin. Invest. 93, 391-396). In this study, the expression of the PGHS-2 gene in response to changes in cell oxidant tone was studied. During LPS exposure, inhibition of synthesis of the free radical, NO., resulted in a small decrease in prostaglandin E2 synthesis that did not reach statistical significance. There was no effect on enzyme mass or mRNA. In contrast, incubation of alveolar macrophages in the presence of LPS plus the antioxidant pyrrolidine dithiocarbamate, the spin trap 5,5-dimethyl-1-pyrroline-N-oxide, or hypoxia, resulted in near complete inhibition of prostaglandin E2 synthesis, PGHS-2 enzyme synthesis, and gene transcription of PGHS-2 mRNA. There was no evidence of cytotoxicity. These results demonstrate that synthesis of PGHS-2 in response to LPS is inhibited by agents that decrease cell oxidant tone.
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PMID:Synthesis of prostaglandin H synthase-2 by human alveolar macrophages in response to lipopolysaccharide is inhibited by decreased cell oxidant tone. 752 41

In view of studies showing that not only nitric oxide synthase (NOS) activity but arginase activity is induced in rodent macrophages by lipopolysaccharide (LPS), the objective of this study was to investigate the co-induction of these two enzymes and to ascertain whether common mechanisms are involved. RAW 264.7 cells were activated by 2 micrograms LPS/ml and incubated for up to 48 hr. Inducible NOS (iNOS) and inducible arginase II (AII) activities were monitored, respectively, by measuring NO2-/NO3- accumulation in cell culture media and formation of urea (as CO2) from L-arginine by cell lysates. AII activity increased linearly up to at least 48 hr, whereas NO2-/NO3- formation reached a plateau well before 48 hr. Immunoprecipitation experiments revealed that AII accounted for 90-100% of arginase activity in LPS-activated macrophages. The inhibitor of NF-kappa B activation, pyrrolidine dithiocarbamate, inhibited the induction of iNOS but not AII. Moreover, whereas IFN-gamma caused iNOS induction, AII induction was nearly abolished by IFN-gamma, perhaps by inhibiting transcription of the AII gene. These observations indicate that co-induction of iNOS and AII occurs by distinct transcriptional mechanisms, AII induction could diminish NO production by decreasing L-arginine availability, and IFN-gamma can prevent AII induction.
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PMID:Co-induction of arginase and nitric oxide synthase in murine macrophages activated by lipopolysaccharide. 753 53

Tissue factor (TF), a 46-kD glycoprotein receptor for coagulation factors VII and VIIa, is expressed on the surface of endothelial cells in response to a variety of agonists and is thought to play an important role in initiating the thrombosis associated with inflammation during infection, sepsis, and organ transplant rejection. The induction of TF activity by lipopolysaccharide (LPS) is regulated, at least partially, at a transcriptional level and an LPS response element containing two activator protein-1 sites and a nuclear factor-kappa B (NF kappa B)-like site has been localized to the 5' flanking region of the TF gene by transfection studies of TF promoter/reporter gene constructs. We have examined the effect of pyrrolidine dithiocarbamate (PDTC), a specific inhibitor of the NF kappa B pathway on the expression of the endogenous TF gene in human umbilical vein endothelial cells (HUVEC). Preincubation of HUVEC for 60 minutes with PDTC inhibited LPS induction of TF activity on the cell surface in a dose-dependent manner, with 50% inhibition occurring at 10 mumol/L PDTC and 100% inhibition at higher concentrations (> or = 100 mumol/L). Furthermore, PDTC inhibited TF expression in response to tumor necrosis factor-alpha, interleukin-1 beta, and phorbol 12-myristate 13-acetate. The effect of PDTC was at the mRNA level, as seen by the complete abrogation of the large increase in TF mRNA observed in LPS-treated HUVEC. These results suggest that endothelial cell activation by diverse agonists initiates intracellular signaling events that converge upon a common pathway involving NF kappa B and, furthermore, that NF kappa B activation is an obligatory step induction of TF.
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PMID:Pyrrolidine dithiocarbamate abrogates tissue factor (TF) expression by endothelial cells: evidence implicating nuclear factor-kappa B in TF induction by diverse agonists. 760 83

Nitric oxide (NO) may be a mediator of beta-cell damage in insulin-dependent diabetes mellitus. beta-Cells express the inducible form of NO synthase (iNOS) and produce large amounts of NO upon exposure to cytokines. iNOS requires the amino acid arginine for NO formation. It has been shown in other cell types that interferon-gamma (IFN gamma) and bacterial lipopolysaccharide induce the enzyme argininosuccinate synthetase (AS), enhancing the capacity of these cells to regenerate arginine from citrulline and maintain NO production in the presence of low arginine concentrations. To characterize the messenger RNA (mRNA) expression of AS in insulin-producing cells, RINm5F cells (RIN cells) were exposed to interleukin-1 beta (IL-1 beta) or to tumor necrosis factor-alpha plus IFN gamma. After 4-6 h, there was a significant and parallel induction of AS and iNOS mRNA. IL-1 beta-induced AS and iNOS mRNA expression was prevented by an inhibitor of the activation factor NF-kappa B pyrrolidine diaminoguanidine, an inhibitor of gene transcription (actinomycin D), and a blocker of protein synthesis (cycloheximide), suggesting coregulation of AS and iNOS by cytokines. RIN cells exposed to IL-1 beta in the presence of citrulline but the absence of arginine had increased AS enzyme activity and produced NO, demonstrating that cytokine-induced AS mRNA expression is accompanied by increased AS activity. Both adult rat islets exposed to IL-1 beta and human pancreatic islets cultured in the presence of IL-1 beta, tumor necrosis factor-alpha, and IFN gamma were able to use citrulline to regenerate arginine and produce NO. Taken as a whole, the present data suggest that regulation of AS activity may play a role in modulation of NO production in both rodent and human insulin-producing cells.
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PMID:Expression of the citrulline-nitric oxide cycle in rodent and human pancreatic beta-cells: induction of argininosuccinate synthetase by cytokines. 762 52

Liver macrophages (Kupffer cells) respond to many stimulations with the production of bioactive substances including cytokines, eicosanoids, and inorganic radicals. In this study the activation of transcription factors by substances inducing cytokine gene expression or superoxide formation in rat Kupffer cells was examined. Using primary cultures of rat Kupffer cells the role of NF-kappa B and activator protein 1 (AP-1) in the expression of the tumor necrosis factor-alpha (TNF-alpha) gene by lipopolysaccharide (LPS) was investigated. Both transcription factors were strongly activated but with different kinetics. Maximal DNA-binding activity was induced with 50 ng of LPS/mL of medium and persisted for at least 24 hours. At that time, NF-kappa B- as well as AP-1-DNA complexes decreased their mobilities in native gels. Among the cytokines tested only TNF-alpha and macrophage colony-stimulating factor (M-CSF) were able to activate NF-kappa B in Kupffer cells. Phorbol ester and zymosan activated AP-1 but not NF-kappa B; the treatment of zymosan yielding a modified form of AP-1. Of all substances found to interfere with TNF-alpha production by Kupffer cells (pyrrolidine dithiocarbamate, dexamethasone, prostaglandin E2, interleukin [IL]-4, IL-10, and transforming growth factor-beta [TGF-beta]) only pyrrolidine dithiocarbamate was able to completely inhibit the activation of NF-kappa B by LPS. Although not abrogating the LPS activation of NF-kappa B, dexamethasone inhibited that of AP-1. The results indicate a direct participation of NF-kappa B in the regulation of TNF-alpha synthesis and a differential effect of LPS on NF-kappa B and AP-1, respectively.
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PMID:Differential activation of transcription factors NF-kappa B and AP-1 in rat liver macrophages. 763 31


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