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)

We have observed a rapid induction of manganese superoxide dismutase (MnSOD) in epithelial, neuronal, and smooth muscle cells (SMC) after acetic acid-induced colitis. To examine the regulation of MnSOD in the SMC more specifically, primary cultures of colonic SMC were developed by enzymatic digestion of the circular muscle layer from an adult rat. SMC were treated for 2-72 h with 0.5 microgram/ml Escherichia coli endotoxin [lipopolysaccharide (LPS)], 10 ng/ml tumor necrosis factor (TNF)-alpha, or 2 ng/ml interleukin-1 beta (IL-1 beta). Cotreatments were performed with IL-1 beta and 4 microM actinomycin or 50 microM cycloheximide. Northern analysis demonstrated 23-fold, 8-fold, and 6-fold inductions of MnSOD mRNA by IL-1 beta, LPS, and TNF-alpha, respectively. Induction of MnSOD by IL-1 beta was eliminated by actinomycin but not by cycloheximide, implicating a requirement for de novo transcription. Western analysis resulted in a 23.7-fold induction of MnSOD protein after 48-h treatment with IL-1 beta. Induction of MnSOD by IL-1 beta and other inflammatory mediators may serve as a protective mechanism to reduce oxygen free radical- and nitric oxide-mediated cell damage during inflammation.
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PMID:Regulation of superoxide dismutase in primary cultures of rat colonic smooth muscle cells. 917 34

To determine which factors are useful for the risk assessment of man-made fibers, we examined the gene expression of proinflammatory cytokines, growth factors, manganese superoxide dismutase (MnSOD), and inducible nitric oxide synthase (iNOS) in mineral fiber-exposed rats by means of reverse transcription-polymerase chain reaction (RT-PCR). Male Wistar rats received a single intratracheal instillation of either saline (control) or two types of fibers (2 mg of Union Internationale Centre le Cancer (UICC) chrysotile or alumina silicate refractory ceramic fiber [RCF]). Expression of interleukin-1 alpha (IL-1 alpha), interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-alpha), platelet-deriving growth factor-A, (PDGF-A), platelet-deriving growth factor-B (PDGF-B), transforming growth factor beta 1 (TGF-beta 1), basic fibroblast growth factor (bFGF), MnSOD, and iNOS mRNA from lung and lipopolysaccharide (LPS)-stimulated alveolar macrophages (AM) were assessed by RT-PCR. Among these factors, IL-1 alpha, TNF-alpha, IL-6, bFGF, and iNOS would be the possible parameters for the risk assessment of fibers. In a follow-up study, we investigated the time course (3 days, 1 week, 1 month, and 3 months) of expression of IL-1 alpha and TNF-alpha by LPS-stimulated AM exposed to mineral fibers in vivo. Male Wistar rats were instilled intratracheally with saline or fibers (2 mg of Union Internationale Contre le Cancer UICC crocidolite or potassium octatitanate whisker [TW]). The expression of IL-1 alpha mRNA by fibers was greatest in TW, crocidolite, chrysotile, and RCF-instilled rat AM, in that order. The increase of IL-1 alpha and TNF-alpha mRNA in AM peaked at 1 month and 3 days after exposure to crocidolite or TW, respectively. The expression of IL-1 alpha by fibers (crocidolite, chrysotile, TW, and RCF) may be a good indicator of the pathologic potential of fibers.
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PMID:Effects of mineral fibers on the expression of genes whose product may play a role in fiber pathogenesis. 940 Jul 19

This study was designed to analyze the association of Nramp1 and/or Lps genes with differential protein expression in macrophages in order to select candidate proteins that might be related to resistance/susceptibility to various microbial infections under the control of the Nramp1 and/or Lps genes. The macrophage cell lines derived from bone marrow of Nramp1 or Lps congenic mice were utilized and high-resolution two-dimensional electrophoreis (2-DE), separating proteins according to their charge and size, was used as a window into alterations in gene expression and a means to compare the macrophages carrying a resistant allele of Nramp1 gene and/or normal allele of Lps gene, with their counterparts carrying either a susceptible allele of Nramp1 or defective allele of the Lps gene. We demonstrate that the changes of constitutive levels of two proteins named according to their isoelectric point/molecular weight (pI/Mr), p6.6/25 and p7.0/22, discriminate satisfactorily not only the macrophages congenic at the Nramp1 gene but also the macrophages congenic at the Lps gene, thus reflecting their common genotype (Nramp1r, Lps[n]). Furthermore, the decreased constitutive levels of these proteins in macrophages carrying a defective allele of Lps but preserving a resistant allele of Nramp1 can be, at least in part, restored by stimulation with interferon gamma or lipopolysaccharide. 2-DE immunoblot analysis identified the p7.0/22 protein as manganese superoxide dismutase. Bcl-2 appears to be the best candidate for p6.6/25 as suggested by 2-DE quantitative alterations and Western blot analysis. These proteins are important in the regulation of intracellular redox balance and the regulation of apoptosis in macrophages and their alterations might reflect closely the transport functions of ions or other charged substrates suggested for Nramp1 protein.
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PMID:Natural resistance to infection with intracellular pathogens: cross-talk between Nramp1 and Lps genes. 952 96

Several recently identified intracellular proteins associate with the tumor necrosis factor (TNF) receptor and activate nuclear transcription factor (NF)-kappaB, c-Jun kinase, and apoptosis. However, the mechanism is not understood. In the present report, we investigated the role of reactive oxygen intermediates in TNF-induced signaling. Overexpression of manganese superoxide dismutase (Mn-SOD) in human breast cancer MCF-7 cells completely abolished TNF-mediated NF-kappaB activation, IkappaB alpha degradation, p65 nuclear translocation, and NF-kappaB-dependent reporter gene expression. Besides TNF, phorbol ester-, okadaic acid-, ceramide-, and lipopolysaccharide-induced activation of NF-kappaB was blocked by Mn-SOD, indicating a common pathway of activation. H2O2-induced NF-kappaB activation, however, was potentiated. In addition, Mn-SOD blocked the TNF-mediated activation of activated protein-1, stress-activated c-Jun protein kinase, and mitogen-activated protein kinase kinase. TNF-induced antiproliferative effects and caspase-3 activation, indicators of apoptosis, were also completely suppressed by transfection of cells with Mn-SOD. Suppression of apoptosis induced by okadaic acid, H2O2, and taxol was also inhibited by Mn-SOD but not that induced by vincristine, vinblastine, or daunomycin. Overall, these results demonstrate that, in addition to several recently identified signaling molecules, reactive oxygen intermediates play a critical role in activation of NF-kappaB, activated protein-1, c-Jun kinase, and apoptosis induced by TNF and other agents.
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PMID:Overexpression of manganese superoxide dismutase suppresses tumor necrosis factor-induced apoptosis and activation of nuclear transcription factor-kappaB and activated protein-1. 958 69

Hyperoxia has deleterious effects on lung form and function; however, the molecular events initiated by oxygen exposure remain unclear. We hypothesized that macrophages function as important intermediaries in the protective response of lung tissues after exposure to hyperoxia. This hypothesis was tested by exposing cultured macrophages (RAW 264.7 cells) to hyperoxia for 24 h and then applying the conditioned medium from these cells to cultured pulmonary epithelial cells or to pulmonary microvascular endothelial cells. We observed that the expression of manganese superoxide dismutase mRNA increased in both target cell lines. Therefore, we next hypothesized that exposure of these macrophages to hyperoxia results in a change in gene expression which could be detected by differential display PCR (ddPCR). This hypothesis was tested by exposing RAW 264.7 cells to > or = 95% oxygen (or normoxia) for 24 h, harvesting RNA, and performing ddPCR. A cDNA fragment upregulated by hyperoxia was identified and reamplified. Verification of differential expression of mRNA was done by Northern analysis. A mRNA which was reproducibly upregulated by hyperoxia, as well as by lipopolysaccharide and interferon gamma, was identified. The differentially expressed PCR product was cloned and sequenced, revealing a product with 99% identity to mouse urokinase mRNA. We speculate that one function of pulmonary macrophages following a hyperoxic exposure is to secrete urokinase.
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PMID:Identification of urokinase as a hyperoxia-inducible gene. 963 98

This study was undertaken to investigate the regulation of mitochondrial manganese superoxide dismutase (Mn-SOD) and cytosolic copper-zinc SOD (Cu,Zn-SOD) in the corpus luteum by inflammatory cytokines. We first examined the developmental expression of both SOD mRNAs in the rat corpus luteum throughout pregnancy. SOD mRNA levels were determined by semiquantitative reverse transcription-polymerase chain reaction. Whereas Cu,Zn-SOD mRNA levels decreased during late pregnancy, Mn-SOD mRNA levels remained elevated. We secondly examined the effects of inflammatory reaction on luteal SODs. Rats received injections of lipopolysaccharide (LPS; 5 mg, i.p.) on Day 15 of pregnancy, and corpora lutea were removed 2 h later. LPS caused an increase in Mn-SOD mRNA levels in the corpus luteum and a decrease in serum progesterone levels, but neither in levels of Cu,Zn-SOD mRNA. To further study the effects of LPS or LPS-induced cytokines, we incubated either whole corpora lutea obtained on Day 15 of pregnancy or a temperature-sensitive simian virus-40 transformed luteal cell line (GG-CL; derived from large luteal cells of the corpus luteum of pregnant rats) in serum-free medium with LPS, interleukin-1alpha (IL-1alpha), IL-beta, IL-6, and tumor necrosis factor alpha. LPS and these cytokines induced a remarkable increase in Mn-SOD mRNA levels in both corpora lutea and GG-CL cells but had no effect on Cu,Zn-SOD mRNA expression. In conclusion, Cu,Zn-SOD and Mn-SOD mRNAs are differently expressed and regulated in the corpus luteum of pregnancy. Mn-SOD mRNA, but not Cu,Zn-SOD mRNA, is highly induced by inflammatory cytokines and may play an important role in protecting luteal cells from inflammation-mediated oxidative damage.
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PMID:Differential regulation of copper-zinc superoxide dismutase and manganese superoxide dismutase in the rat corpus luteum: induction of manganese superoxide dismutase messenger ribonucleic acid by inflammatory cytokines. 967 14

Our group recently reported that cultured sheep pulmonary artery endothelial cells (SPAECs) became resistant to lipopolysaccharide (LPS)-induced apoptosis several days after constitutive synthesis of nitric oxide (NO) after adenoviral (Ad) transfer of inducible NO synthase (iNOS) or exposure to the NO donor S-nitroso-N-acetylpenicillamine (SNAP) (E. Tzeng, Y.-M. Kim, B. R. Pitt, A. Lizonova, I. Kovesdi, and T. R. Billiar. Surgery 122: 255-263, 1997). In the present study, we confirmed this observation by establishing stable transfectants after retroviral gene transfer [replication-deficient retrovirus (DFG)] of human iNOS (DFG-iNOS) SPAECs and then used all three approaches (Ad, DFG, and SNAP) to determine underlying mechanisms of this phenomenon. Continuous endogenous production of NO in itself did not cause apoptosis as assessed by phase-contrast microscopy, nuclear morphology, and internucleosomal DNA fragmentation. Prolonged (72-96 h) synthesis of NO, however, after DFG- or replication-deficient adenovirus (Ad. CMV)-iNOS or SNAP (100 microM, 96 h) inhibited LPS-induced apoptosis. The kinetics of such protection suggested that NO may be inducing other gene products. Ad-mediated transfer of manganese superoxide dismutase (MnSOD) decreased the sensitivity of wild-type SPAECs to LPS-induced apoptosis. MnSOD, however, was not induced in an NG-monomethyl-L-arginine (L-NMMA)-sensitive time-dependent fashion after Ad.CMV-iNOS. Other inducible genes that may be affected by NO and that may protect against potential oxidant-mediated LPS-induced apoptosis including 70-kDa heat shock protein, heme oxygenase-1, metallothionein, and Bcl-2 also were not elevated in an L-NMMA-sensitive, time-dependent fashion. Although the candidate gene product underlying NO-induced protection remains unclear, we did note that prolonged synthesis of NO inhibited LPS-induced activation of an interleukin-1beta-converting enzyme-like cysteine protease (cysteine protease protein-32-like) in a dithiothreitol-sensitive fashion, suggesting that S-nitrosylation of an important downstream target of convergence of apoptotic signals may contribute to the sensitivity of SPAECs to LPS.
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PMID:Nitric oxide inhibits lipopolysaccharide-induced apoptosis in pulmonary artery endothelial cells. 975 4

Bacterial lipopolysaccharide can induce manganese superoxide dismutase (MnSOD) gene expression in a variety of cells. Paclitaxel (taxol) shares many properties of lipopolysaccharide. Here we report that paclitaxel can induce MnSOD gene expression in human lung adenocarcinoma cell line A549 in a time- and dose-dependent manner. Additional anticancer drugs, vinblastine and vincristine, also induced MnSOD gene expression. We have shown previously (Das, K. C., and White, C. W. (1997) J. Biol. Chem. 272, 14914-14920) that these drugs can activate protein kinase C (PKC). The PKC agonists thymeleatoxin (0.5 microM) and 12-deoxyphorbol 13-phenylacetate 20-acetate (dPPA; 10 nM) potently induced MnSOD gene expression. Calphostin C and GF109203X, both specific inhibitors of PKC, each inhibited MnSOD gene expression by anticancer agents. Down-regulation of PKC by prolonged treatment with phorbol 12-myristate 13-acetate (PMA) also inhibited induction of MnSOD by anticancer drugs, indicating an important role of PKC in MnSOD signaling by these agents. Of 11 PKC isoenzymes, only PKCdelta translocated to the cell membrane after stimulation with anticancer drugs. By contrast, dPPA, PMA, and thymeleatoxin caused translocation of PKCalpha, betaI, delta, and mu isotypes. Anticancer drug-stimulated cells also had increased total PKC activity in membrane and cytosolic fractions. Thus, paclitaxel, vinblastine, and vincristine each specifically activate PKCdelta, whereas PMA, thymeleatoxin, and dPPA activate multiple isoenzymes. PKCdelta was the only isoform activated by each agent in both groups of compounds effective in MnSOD induction.
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PMID:Protein kinase Cdelta-dependent induction of manganese superoxide dismutase gene expression by microtubule-active anticancer drugs. 985 37

Mitochondrial manganese superoxide dismutase (Mn-SOD) is the primary cellular defense against damaging superoxide radicals generated by aerobic metabolism and as a consequence of inflammatory disease. Elevated expression of Mn-SOD therefore provides a potent cytoprotective advantage during acute inflammation. Mn-SOD contains a GC-rich and TATA/CAAT-less promoter characteristic of a housekeeping gene. In contrast, however, Mn-SOD expression is dramatically regulated in a variety of cells by numerous proinflammatory mediators, including lipopolysaccharide, tumor necrosis factor-alpha, and interleukin-1. To understand the underlying regulatory mechanisms controlling Mn-SOD expression, we utilized DNase I-hypersensitive (HS) site analysis, which revealed seven hypersensitive sites throughout the gene. Following high resolution DNase I HS site analysis, the promoter was found to contain five HS subsites, including a subsite that only appears following stimulus treatment. Dimethyl sulfate in vivo footprinting identified 10 putative constitutive protein-DNA binding sites in the proximal Mn-SOD promoter as well as two stimulus-specific enhanced guanine residues possibly due to alterations in chromatin structure. In vitro footprinting data implied that five of the binding sites may be occupied by a combination of Sp1 and gut-enriched Kr uppel-like factor. These studies have revealed the complex promoter architecture of a highly regulated cytoprotective gene.
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PMID:In vivo architecture of the manganese superoxide dismutase promoter. 992 Aug 76

Initiation of nitric oxide (NO.)-mediated apoptotic cell death in RAW 264.7 macrophages is associated with up-regulation of mitochondrial manganese superoxide dismutase (MnSOD; SOD2) and down-regulation of cytosolic copper zinc superoxide dismutase (CuZnSOD; SOD1) at their individual mRNA and protein levels. To evaluate the decreased CuZnSOD expression and the initiation of apoptosis we stably transfected macrophages to overexpress human CuZnSOD. Individual clones revealed a 2-fold increase in CuZnSOD activity. Expression of a functional and thus protective CuZnSOD was verified by attenuated superoxide (O2(.)-)-mediated apoptotic as well as necrotic cell death. In this study we showed that SOD-overexpressing macrophages (R-SOD1-12) were also protected against NO.-initiated programmed cell death. Protection was substantial towards NO. derived from exogenously added NO donors or when NO. was generated by inducible NO synthase activation, and was evident at the level of p53 accumulation, caspase activation and DNA fragmentation. Stimulation of parent and SOD-overexpressing cells with a combination of lipopolysaccharide and murine interferon gamma produced equivalent amounts of nitrite/nitrate, which ruled out attenuated inducible NO. synthase activity during protection. Because protection by a O2(.)--scavenging system during NO. -intoxication implies a role of NO. and O2(.)- in the progression of cell damage, we used uric acid to delineate the role of peroxynitrite during NO.-elicited apoptosis. The peroxynitrite scavenger uric acid left S-nitrosoglutathione or spermine-NO-elicited apoptosis unaltered, blocking only 3-morpholinosydnonimine-mediated cell death. As a result we exclude peroxynitrite from contributing, to any major extent, to NO. -mediated apoptosis. Therefore protection observed with CuZnSOD overexpression is unlikely to stem from interference with peroxynitrite formation and/or action. Unequivocally, the down-regulation of CuZnSOD is associated with NO. cytotoxicity, whereas CuZnSOD overexpression protects macrophages from apoptosis.
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PMID:Overexpression of CuZn superoxide dismutase protects RAW 264.7 macrophages against nitric oxide cytotoxicity. 1002 4


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