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)

Normal mouse embryo fibroblasts (MEF) are killed by treatment with low doses of interferon gamma (IFN-gamma) in combination with lipopolysaccharide (LPS). This cytotoxicity has previously been shown to represent an active suicidal reaction. Here we show that the time period between first contact with IFN-gamma/LPS (t = 0 h) and cell death (t = 48 h) can be separated into two distinct periods, during which glycolytic metabolism of glucose either has a positive (8-24 h) or a negative (30-48 h) effect on cytotoxicity. During the first period (8-24 h), withdrawal of glucose from the culture medium, or inclusion in the medium of the glycolytic inhibitors deoxy-D-glucose, NaF or iodoacetate, prevented later cell death. During the second period (30-48 h), withdrawal of glucose or supplementation of the culture medium with glycolytic inhibitors was no longer protective; instead it was a requirement for cell suicide to occur. Glycolytic activity during the first period was found to be increased twofold in LPS-treated MEF and almost threefold in IFN-gamma/LPS-treated MEF. A variety of agents were found both to protect cells against IFN-gamma/LPS-induced cytotoxicity and to inhibit increased glycolysis in these cells: glucocorticoids, the serine-type protease inhibitor N-acetyl-DL-phenylalanine-beta-naphthyl ester, the ADP-ribosylation inhibitors 3-aminobenzamide and nicotinamide, and the transcription and translation inhibitors actinomycin and cycloheximide. Mitochondrial function, although normal in LPS-treated cells, was markedly depressed in IFN-gamma/LPS-treated MEF. Specifically, malate- and succinate-driven respiration was found to be impaired. Furthermore, IFN-gamma/LPS-treated MEF contained one-third of the ATP level of LPS-treated MEF. Withdrawal of L-arginine from the culture medium prevented cell death in IFN-gamma/LPS-treated MEF. N-Methyl-L-arginine, which is an inhibitor of nitric oxide (NO.) biosynthesis from L-arginine, also inhibited cell death. In conclusion, we propose that cell death in our experiments is due to an L-arginine/glycolysis-dependent impairment of mitochondrial respiration.
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PMID:Interferon-gamma/lipopolysaccharide-treated mouse embryonic fibroblasts are killed by a glycolysis/L-arginine-dependent process accompanied by depression of mitochondrial respiration. 193 71

We describe here the involvement of calcium-activated neutral protease (CANP or calpain, EC 3.4.22.17) in calcium-dependent proteolytic processing of the precursor of human interleukin 1 alpha (IL-1 alpha) into mature IL-1 alpha. Calcium ionophore ionomycin enhanced proteolytic processing of pre-IL-1 alpha and the release of mature IL-1 alpha either from lipopolysaccharide (LPS)-activated human adherent mononuclear cells or from a human bladder carcinoma cell line (HTB9 5637) that constitutively produces human IL-1 alpha and -beta. The proteolytic processing of pre-IL-1 alpha was completely inhibited by EGTA. Similar calcium-dependent proteolytic processing of pre-IL-1 alpha was also observed with lysates of either LPS-activated human adherent mononuclear cells or HTB9 5637 cells. Since the optimal pH for processing was between 7 and 8, and E-64 (a cysteine protease inhibitor) and leupeptin (a serine and cysteine protease inhibitor) both inhibited this processing by cell lysates, we hypothesized that a calcium-activated neutral protease, CANP, might be responsible for this processing. This hypothesis was supported by data showing that the specific CANP inhibitor peptide inhibited this proteolysis in cell lysates in a dose-dependent fashion (IC50 = 0.05 microM) and that treatment of pre-IL-1 alpha with purified CANP yielded the 17-kDa mature form of IL-1 alpha, which has an amino terminus identical with that reported for mature human IL-1 alpha. Taken together, these findings indicate that calcium-dependent proteolytic processing of pre-IL-1 alpha is selectively mediated by CANP.
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PMID:Identification of calcium-activated neutral protease as a processing enzyme of human interleukin 1 alpha. 211 74

The nucleotide sequences of two mink serum amyloid A (SAA) cDNA clones have been analyzed, one (SAA1) 776 base pairs long and the other (SAA2) 552 base pairs long. Significant differences were discovered when derived amino acid sequences were compared with data for apoSAA isolated from high density lipoprotein. Previous studies of mink protein SAA and amyloid protein A (AA) suggest that only one SAA isotype is amyloidogenic. The cDNA clone for SAA2 defines the "amyloid prone" isotype while SAA1 is found only in serum. Mink SAA1 has alanine in position 10, isoleucine in positions 24, 67, and 71, lysine in position 27, and proline in position 105. Residue 10 in mink SAA2 is valine while arginine and asparagine are at positions 24 and 27, respectively, all characteristics of protein AA isolated from mink amyloid fibrils. Mink SAA2 also has valine in position 67, phenylalanine in position 71, and amino acid 105 is serine. It remains unknown why these six amino acid substitutions render SAA2 more amyloidogenic than SAA1. Eighteen hours after lipopolysaccharide stimulation, mink SAA mRNA is abundant in liver with relatively minor accumulations in brain and lung. Genes encoding both SAA isotypes are expressed in all three organs while no SAA mRNA was detectable in amyloid prone organs, including spleen and intestine, indicating that deposition of AA from locally synthesized SAA is unlikely. A third mRNA species (2.2 kilobases) was identified and hybridizes with cDNA probes for mink SAA1 and SAA2. In addition to a major primary translation product (molecular mass 14,400 Da) an additional product with molecular mass 28,000 Da was immunoprecipitable.
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PMID:Mink serum amyloid A protein. Expression and primary structure based on cDNA sequences. 235 48

alpha-N-(3-Acyloxyacyl)-ornithine (or -serine) is the structure of lipoamino acids obtained by us previously from some gram-negative bacteria (Y. Kawai and I. Yano, Eur. J. Biochem. 136:531-538, 1983; Y. Kawai, I. Yano, and K. Kaneda, Eur. J. Biochem. 171:73-80, 1988; Y. Kawai, I. Yano, K. Kaneda, and E. Yabuuchi, Eur. J. Biochem. 175:633-641, 1988). The 3-acyloxyacylamide structure is present in both the lipoamino acids and lipid A of lipopolysaccharide (endotoxin). The efficacy of lipoamino acids (an ornithine-containing lipid and a serine-containing lipid) in activating C3H/HeSlc mouse peritoneal exudate macrophages was compared with that of bacterial lipopolysaccharide, because the two types of substances were expected to exhibit similar biological activities and physiological functions on the basis of their structural similarities. Actually, the lipoamino acids, as well as lipopolysaccharide, strongly activated the macrophages to generate the immunoregulatory substances prostaglandin E2 and interleukin-1, but their effect on the induction of L929 cell cytolytic factor (a possible tumor necrosis factor), another immunoregulatory substance, was weaker than that of lipopolysaccharide. The effect of lipoamino acids on the cytotoxicity of macrophages for EL-4 leukemia cells was very weak. However, all of these activities, as far as tested, were strongly enhanced by synergistic action with gamma interferon. Only the serine-containing lipid killed both C3H/HeSlc and C3H/HeJ macrophages to almost the same degree as endotoxin killed C3H/HeSlc macrophages. On the other hand, lethal toxicity for mice was not found with either the ornithine-containing lipid or the serine-containing lipid, even when 7 mg of compound was injected into a mouse. These studies suggest that the lipoamino acids are nontoxic characteristic immunoactivators.
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PMID:Macrophage activation by an ornithine-containing lipid or a serine-containing lipid. 249 44

M1 cells derived from mouse myeloid leukemia have been reported to differentiate to macrophage-like cells upon treatment with substances such as lipopolysaccharide. Previously we found that in mouse peritoneal macrophages most of the neutral amino acids were taken up through a unique Na+-independent system. In this paper we have investigated the neutral amino acid transport in M1 cells and in those treated with lipopolysaccharide. In M1 cells serine, alanine and proline were taken up mainly by Na+-dependent transport systems, and leucine was largely transported by a Na+-independent system. By treating the cells with lipopolysaccharide, the activities of the Na+-dependent systems markedly decreased, whereas the activity of the Na+-independent system was little affected. The amino acid concentrations in the cells and the culture medium were measured. As a whole, the intracellular to extracellular distribution ratios for neutral amino acids that are preferred substrates for Na+-dependent systems were decreased on lipopolysaccharide treatment, whereas those for amino acids that are mainly transported by a Na+-independent system were slightly increased. From these results we conclude that M1 cells treated with lipopolysaccharide tend to differentiate to macrophage-like cells with respect to the neutral amino acid transport.
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PMID:Changes in neutral amino acid transport activity in myeloid leukemia cells differentiated by lipopolysaccharide. 250 38

The long term (18 day) metabolic response of bovine articular cartilage to treatment with either E. Coli lipopolysaccharide (LPS) or interleukin 1 was studied. For LPS treatment, incorporation of [35S]sulfate into the large proteoglycan population was inhibited 80% while that into the small interstitial proteoglycans was only inhibited 40%. Incorporation of [3H]serine into the large proteoglycan population was inhibited approximately 72% while incorporation into other protein was inhibited only 16%. Furthermore, the rate of catabolism of [3H]serine labeled proteoglycans was increased 2-fold by LPS treatment while the rate of 3H-labeled general protein catabolism was not affected. Incorporation of [3H]glucosamine into hyaluronate was increased; however a correction for changes in the specific activity of the intracellular [3H]glucosamine precursor pool in LPS-treated cultures indicated that the net amount of hyaluronate synthesized was not altered by LPS treatment. The 3H/35S ratios in isolated chondroitin sulfate disaccharides labeled with [35S]sulfate and [3H]glucosamine precursors were significantly changed during long term LPS treatment, suggesting that general carbohydrate pathways are altered. The 3H/35S changes were larger in the disaccharides isolated from the small proteoglycans indicating that different precursor pools, probably in different cell populations, preferentially synthesize this proteoglycan population. Interleukin-1 affected the same chondrocytic pathways as LPS as shown by a) the extent of inhibition of proteoglycan synthesis, b) the selective inhibition of synthesis of the large proteoglycan species, c) acceleration of proteoglycan catabolism, d) net depletion of proteoglycans from the tissue, e) increases in guanidine HCl extractable [3H]hyaluronate, f) increases in levels of prostaglandin E2 synthesis, g) changes in 3H/35S ratios in glycosaminoglycan chains and, h) minimal effects on general protein synthesis.
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PMID:Effects of interleukin-1 and lipopolysaccharides on protein and carbohydrate metabolism in bovine articular cartilage organ cultures. 250 33

Bone marrow-derived macrophages were used to study the mechanism of action of recombinant gamma interferon associated with multilamellar phospholipid liposomes. Gamma interferon associated with liposomes caused an inhibition of [3H]-thymidine uptake induced by macrophage colony-stimulating factor (CSF-1), and primed macrophages for subsequent induction of tumoricidal activity by bacterial lipopolysaccharide (LPS). The liposomes were equally active whether the gamma interferon was added before, or after vesicle formation. The result suggested that significant biologically active gamma interferon was bound to the outside of the vesicles. Interferon binding to liposomes was confirmed using radiolabelled ligand. The liposomes themselves were found to be biologically active in promoting proliferation and in acting synergistically to prime cytotoxicity. Vesicles that contained both phosphatidylethanolamine and phosphatidyl-serine or succinylated phosphatidylethanolamine were most active. Such vesicles were found to be internalised rapidly by bone marrow-derived macrophages. Thus, encapsulation of ligand, and internalisation into cytoplasm, do not appear to be involved in the action of liposome-associated gamma interferon. On the other hand, the liposomes may contribute in other ways to improving the therapeutic potential of gamma interferon.
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PMID:Encapsulation is not involved in the activities of recombinant gamma interferon associated with multilamellar phospholipid liposomes on murine bone marrow-derived macrophages. 250 21

Binding of tumor necrosis factor-alpha (TNF-alpha) to its receptor on U937 cells results in rapid and TNF dose-dependent phosphorylation of a cytosolic protein with an apparent molecular mass of 26,000 kDa (p26) and an isoelectric point of 5.6. Half-maximal phosphorylation of p26 was achieved at concentrations of 1.8 ng/ml and was detectable within 20 s of TNF-alpha treatment. p26 is phosphorylated exclusively at serine residues. p26 phosphorylation occurs at 37 degrees C as well as at 14 degrees C, indicating that internalization of the TNF receptor is not required for serine kinase activation. Dephosphorylation of p26 starts 10 min after TNF-induced phosphorylation, suggesting a possible regulatory function of this cytosolic protein within the post-TNF receptor signaling system. p26 is also phosphorylated upon treatment with lymphotoxin. In contrast, both interferon-gamma and lipopolysaccharide fail to induce p26 phosphorylation. Whereas phosphorylated p26 was detected in the TNF-sensitive breast cancer cell line CRL1500, other TNF-responsive tumor cell lines investigated lacked enhanced phosphorylation of p26 in response to TNF, indicating that the 26-kDa phosphoprotein (pp26) may be a cell type-specific second messenger molecule involved in TNF signal transduction in some, but not all, target cells. p26 is also phosphorylated in a subclone of U937 (U937.C27) that responds to TNF-alpha with differentiation, yet is resistant to TNF-alpha-mediated growth inhibition. In contrast, p26 is not phosphorylated in another U937 derivative (U937.G3) that is resistant to both TNF-alpha-induced growth arrest and differentiation, suggesting that pp26 may play a role in the TNF signaling pathway linked to differentiation processes rather than to growth control.
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PMID:Tumor necrosis factor signal transduction. Tissue-specific serine phosphorylation of a 26-kDa cytosolic protein. 253 51

Bacterial lipopolysaccharide (LPS) potentiates protein kinase C (PKC)-dependent responses such as the activation of arachidonic acid metabolism in macrophages (Aderem, A. A., Cohen, D. S., Wright, S. D., and Cohn, Z. A. (1986) J. Exp. Med. 164, 165-179). Concomitantly, LPS promotes the myristoylation of a 68K PKC substrate, shown to be equivalent to the 80/87K PKC substrate found in brain and fibroblasts (Aderem, A. A., Albert, K. A., Keum, M. M., Wang, J. K., Greengard, P., and Cohn, Z. A. (1988) Nature 332, 362-364). We have now examined the effect of LPS on the phosphorylation of this 68K PKC substrate. We report here that LPS modifies the kinetics and extent of phosphorylation of the 68K protein. While treatment with LPS alone induces low level phosphorylation of the 68K protein, it markedly increases the rate of subsequent phorbol 12-myristate 13-acetate (PMA)-dependent phosphorylation of this protein. Phosphorylation in LPS-treated macrophages was maximal 1-2 min after administration of PMA, while maximal phosphorylation in macrophages not exposed to LPS was only achieved 6 min after addition of PMA. In addition to increasing the rate of PMA-dependent phosphorylation of the 68K protein in macrophages, LPS also promoted the phosphorylation of a novel peptide on the 68K protein. Thus while PMA stimulated the phosphorylation of two thermolytic phosphopeptides (phosphopeptides 1 and 2), the low level of phosphorylation observed with LPS alone was found to occur on phosphopeptides 1 and 2 as well as on a novel phosphopeptide (phosphopeptide 3). Furthermore, LPS treatment of macrophages potentiated phosphorylation of all three phosphopeptides when the cells were subsequently stimulated with PMA. While phosphorylation stimulated by LPS and PMA was slightly more than additive for phosphopeptides 1 and 2, it was markedly synergistic (increased 14.5-fold) for phosphopeptide 3. Phosphorylation of all three phosphopeptides occurred exclusively on serine. It is possible that LPS-induced myristoylation of the 68K protein directs it to the membrane where its phosphorylation is enhanced by its close association with PKC.
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PMID:Bacterial lipopolysaccharide regulates the phosphorylation of the 68K protein kinase C substrate in macrophages. 272 20

Guinea pig endotoxicosis induced by lipopolysaccharide from Coxiella burnetii Nine Mile phase I stimulates phosphorylation of liver ribosomal protein S6, with a 50% increase at 12 h postinoculation. The responsible protein kinase (S6PK) has been partially purified from liver; its activity is independent of cyclic AMP and of Ca2+ plus phosphatidyl serine or diacylglycerol. The preparation has an apparent optimum concentration of 20 mM Mg2+, while Ca2+ and Mn2+ are each inhibitory at 2 mM. The apparent Km for ATP is 30 microM with intact ribosomes. Because of the central role of phosphorylation in metabolic regulation and a purported role of phosphorylated S6 in protein synthesis, the lipopolysaccharide-induced stimulation of S6PK suggests a significant regulatory role of such enzymes in the pathobiochemistry of Q fever infection and endotoxicosis.
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PMID:Endotoxicosis induced by Coxiella burnetii lipopolysaccharide stimulates a ribosomal protein S6 kinase: some properties of the partially purified enzyme. 280 43


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