Journal articles on the topic 'LPS- binding proteins'
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1
Fenton, Matthew J., and Douglas T. Golenbock. "LPS-binding proteins and receptors." Journal of Leukocyte Biology 64, no. 1 (July 1998): 25–32. http://dx.doi.org/10.1002/jlb.64.1.25.
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Hailman, E., H. S. Lichenstein, M. M. Wurfel, D. S. Miller, D. A. Johnson, M. Kelley, L. A. Busse, M. M. Zukowski, and S. D. Wright. "Lipopolysaccharide (LPS)-binding protein accelerates the binding of LPS to CD14." Journal of Experimental Medicine 179, no. 1 (January 1, 1994): 269–77. http://dx.doi.org/10.1084/jem.179.1.269.
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CD14 is a 55-kD protein found as a glycosylphosphatidylinositol (GPI)-anchored protein on the surface of monocytes, macrophages, and polymorphonuclear leukocytes, and as a soluble protein in the blood. Both forms of CD14 participate in the serum-dependent responses of cells to bacterial lipopolysaccharide (LPS). While CD14 has been described as a receptor for complexes of LPS with LPS-binding protein (LBP), there has been no direct evidence showing whether a ternary complex of LPS, LBP, and CD14 is formed, or whether CD14 binds LPS directly. Using nondenaturing polyacrylamide gel electrophoresis (native PAGE), we show that recombinant soluble CD14 (rsCD14) binds LPS in the absence of LBP or other proteins. Binding of LPS to CD14 is stable and of low stoichiometry (one or two molecules of LPS per rsCD14). Recombinant LBP (rLBP) does not form detectable ternary complexes with rsCD14 and LPS, but it does accelerate the binding of LPS to rsCD14. rLBP facilitates the interaction of LPS with rsCD14 at substoichiometric concentrations, suggesting that LBP functions catalytically, as a lipid transfer protein. Complexes of LPS and rsCD14 formed in the absence of LBP or other serum proteins strongly stimulate integrin function on PMN and expression of E-selectin on endothelial cells, demonstrating that LBP is not necessary for CD14-dependent stimulation of cells. These results suggest that CD14 acts as a soluble and cell surface receptor for LPS, and that LBP may function primarily to accelerate the binding of LPS to CD14.
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Qureshi, N., P. Y. Perera, J. Shen, J. J. Gao, A. Dhar, S. N. Vogel, and D. C. Morrison. "NOVEL LPS-BINDING PROTEINS IN MURINE MACROPHAGES." Shock 17, Supplement (June 2002): 28. http://dx.doi.org/10.1097/00024382-200206001-00082.
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Lei, M. G., and D. C. Morrison. "Specific endotoxic lipopolysaccharide-binding proteins on murine splenocytes. II. Membrane localization and binding characteristics." Journal of Immunology 141, no. 3 (August 1, 1988): 1006–11. http://dx.doi.org/10.4049/jimmunol.141.3.1006.
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Abstract We have characterized the binding of LPS to an 80-kDa LPS-binding protein detected by an LPS photoaffinity probe to be present on murine splenocytes. Specific binding of LPS to the 80-kDa protein is directly proportional to LPS concentration at low concentrations of LPS and is saturable at high concentrations of LPS. Binding is inhibited by both homologous and heterologous underivatized LPS as well as by polysaccharide-free lipid A, indicating a specificity for the biologically active component of LPS. Analysis of the kinetics of binding indicate a time-dependent increase over the first 15 min, but increases are not detected after this time. Binding of LPS to the 80-kDa LPS-binding protein is reduced but still readily detectable at 4 degrees C in the presence of azide. The presence of the 80-kDa LPS-binding protein in an isolated cytoplasmic membrane fraction of murine splenocytes as well as its release from intact splenocytes by octylglucoside suggest that this LPS-binding protein is membrane localized. The results are consistent with, but do not establish unequivocally, the identity of the 80-kDa LPS-binding protein as a specific membrane receptor for lipid A.
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Schumann, R. R., N. Lamping, and A. Hoess. "Interchangeable endotoxin-binding domains in proteins with opposite lipopolysaccharide-dependent activities." Journal of Immunology 159, no. 11 (December 1, 1997): 5599–605. http://dx.doi.org/10.4049/jimmunol.159.11.5599.
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Abstract Host defense against microorganisms involves proteins that bind specifically to bacterial endotoxins (LPS), causing different cellular effects. Although LPS-binding protein (LBP) can enhance LPS activities, while bactericidal/permeability-increasing protein (BPI) and Limulus anti-LPS factor (LALF) neutralize LPS, it has been proposed that their LPS-binding domains possess a similar structure. Here, we provide evidence that the LBP/LPS-binding domain is, as in the LALF structure, solvent exposed and therefore available for LPS binding. Our investigations into the activity of LPS-binding domains of different LPS-binding proteins, in the context of LBP, provide the first functional analysis of these domains in a whole protein. We constructed domain exchange hybrid proteins by substituting 12 amino acids of the LBP/LPS-binding domain with those of BPI and LALF and expressed them in Chinese hamster ovary cells. Although discrete point mutations within the LPS-binding domain of LBP disrupted its specific functions, the hybrid proteins were still able to bind LPS and, in addition, retained the wild-type LBP activity of enhancing LPS priming for FMLP-induced oxygen radical production by neutrophils and transferring LPS aggregates to CD14. Although BPI and LALF display opposite activities to LBP, and LALF does not share any sequence homology with LBP, our data provide strong evidence that LBP, BPI, and LALF possess a solvent-exposed, interchangeable LPS binding motif that is functionally independent of LPS transport or neutralization.
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Hoess, A., Ch Ried, C. Wahl, R. Liddington, H. Wagner, and L. Schneider-Mergener. "110 THE LPS-BINDING DOMAIN OF ENDOTOXIN NEUTRALISING PROTEINS." Shock 3, no. 5 (May 1995): 34. http://dx.doi.org/10.1097/00024382-199505000-00111.
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Elass-Rochard, Elisabeth, Dominique Legrand, Valerie Salmon, Anca Roseanu, Mihaela Trif, Peter S. Tobias, Joel Mazurier, and Genevieve Spik. "Lactoferrin Inhibits the Endotoxin Interaction with CD14 by Competition with the Lipopolysaccharide-Binding Protein." Infection and Immunity 66, no. 2 (February 1, 1998): 486–91. http://dx.doi.org/10.1128/iai.66.2.486-491.1998.
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ABSTRACT Human lactoferrin (hLf), a glycoprotein released from neutrophil granules during inflammation, and the lipopolysaccharide (LPS)-binding protein (LBP), an acute-phase serum protein, are known to bind to the lipid A of LPS. The LPS-binding sites are located in the N-terminal regions of both proteins, at amino acid residues 28 to 34 of hLf and 91 to 108 of LBP. Both of these proteins modulate endotoxin activities, but they possess biologically antagonistic properties. In this study, we have investigated the competition between hLf and recombinant human LBP (rhLBP) for the binding of Escherichia coli 055:B5 LPS to the differentiated monocytic THP-1 cell line. Our studies revealed that hLf prevented the rhLBP-mediated binding of LPS to the CD14 receptor on cells. Maximal inhibition of LPS-cell interactions by hLf was raised when both hLf and rhLBP were simultaneously added to LPS or when hLf and LPS were mixed with cells 30 min prior to the incubation with rhLBP. However, when hLf was added 30 min after the interaction of rhLBP with LPS, the binding of the rhLPS-LBP complex to CD14 could not be reversed. These observations indicate that hLf competes with rhLBP for the LPS binding and therefore interferes with the interaction of LPS with CD14. Furthermore, experiments involving competitive binding of the rhLBP-LPS complex to cells with two recombinant mutated hLfs show that in addition to residues 28 to 34, another basic cluster which contains residues 1 to 5 of hLf competes for the binding to LPS. Basic sequences homologous to residues 28 to 34 of hLf were evidenced on LPS-binding proteins such as LBP, bactericidal/permeability-increasing protein, and Limulus anti-LPS factor.
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El-Samalouti, Volker T., Jens Schletter, Helmut Brade, Lore Brade, Shoichi Kusumoto, Ernst T. Rietschel, Hans-Dieter Flad, and Artur J. Ulmer. "Detection of Lipopolysaccharide(LPS)-Binding Membrane Proteins by Immuno-Coprecipitation with LPS and Anti-LPS Antibodies." European Journal of Biochemistry 250, no. 2 (December 1997): 418–24. http://dx.doi.org/10.1111/j.1432-1033.1997.0418a.x.
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Amura, Claudia R., Takayuki Kamei, Noriko Ito, Michael J. Soares, and David C. Morrison. "Differential Regulation of Lipopolysaccharide (LPS) Activation Pathways in Mouse Macrophages by LPS-Binding Proteins." Journal of Immunology 161, no. 5 (September 1, 1998): 2552–60. http://dx.doi.org/10.4049/jimmunol.161.5.2552.
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Abstract LPS binding to its receptor(s) on macrophages induces the synthesis of inflammatory mediators involved in septic shock. While the signaling mechanism(s) remains to be fully defined, the human LPS-binding protein (LBP) is known to regulate responses to LPS by facilitating its binding to CD14 on human monocytes. The structurally related bactericidal permeability increasing protein (BPI) differs from LBP by inhibiting LPS-induced human monocyte activation. We have demonstrated that, unlike the human monocyte response to LPS, both LBP and BPI inhibited LPS-stimulated TNF-α production in mouse peritoneal macrophages. In contrast, LPS-dependent nitric oxide release was not affected by LBP. LPS induces the phosphorylation of a number of proteins in a dose and time-dependent manner, however, the pattern of LPS-induced phosporylation was not reduced by either LBP or BPI under conditions that result in selective TNF-α inhibition. Further, activation of the transcription factor NF-κB in response to LPS was also not modified by either LBP or BPI. Finally, no differences were detected in TNF-α or inducible nitric oxide synthase mRNA accumulations induced by LPS in the presence or absence of either protein, whereas a slight decreased mRNA stability was observed in the group with LPS treatment. These results would suggest that many of the early signaling events contribute to LPS-induced macrophage signaling at a point preceding the divergence of pathways that differentially regulate TNF-α and NO production.
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Lamping, N., A. Hö, B. Yu, T. C. Park, S. D. Wright, C. Kirschning, D. Pfeil, F. Herrmann, and R. R. Schumann. "IDENTIFICATION OF THE LIPOPOLYSACCHARIDE (LPS) BINDING SITE OF LPS BINDING PROTEIN (LBP) BY SITE-DIRECTED MUTAGENESIS, EVIDENCE FOR A SIMILAR LPS RECOGNITION MECHANISM IN DIFFERENT LPS BINDING PROTEINS." Shock 7, Supplement (March 1997): 21–22. http://dx.doi.org/10.1097/00024382-199703001-00087.
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Lei, M. G., and D. C. Morrison. "Specific endotoxic lipopolysaccharide-binding proteins on murine splenocytes. I. Detection of lipopolysaccharide-binding sites on splenocytes and splenocyte subpopulations." Journal of Immunology 141, no. 3 (August 1, 1988): 996–1005. http://dx.doi.org/10.4049/jimmunol.141.3.996.
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Abstract Experiments have been carried out using a unique radio-iodinated, disulfide-reducible, photoactivatable LPS derivative (ASD-LPS) to detect specific LPS-binding proteins on murine splenocytes. Fractionation of LPS-photo-cross-linked, reduced, and solubilized splenocyte extracts on two-dimensional polyacrylamide gels has allowed the identification of an 80-kDa LPS-binding protein with approximate pI of 6.5. This LPS-binding protein is present on partially purified populations of splenic B lymphocytes, T lymphocytes, and macrophages. It is also the dominant LPS-binding protein on the murine 70Z/3 B cell line and the YAC-1 and EL4 T cell lines but is not detectable on the undifferentiated murine Sp2/0 myeloma cell line. Of potential importance is the fact that the 80-kDa protein appears to be indistinguishable when photolabeled extracts of splenocytes from the C3HeB/FeJ (lpsn) and LPS-nonresponder C3H/HeJ (lpsd) mice are compared.
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Weersink, A. J., K. P. van Kessel, M. E. van den Tol, J. A. van Strijp, R. Torensma, J. Verhoef, P. Elsbach, and J. Weiss. "Human granulocytes express a 55-kDa lipopolysaccharide-binding protein on the cell surface that is identical to the bactericidal/permeability-increasing protein." Journal of Immunology 150, no. 1 (January 1, 1993): 253–63. http://dx.doi.org/10.4049/jimmunol.150.1.253.
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Abstract Several LPS-binding proteins have been identified on the surface of human granulocytes (polymorphonuclear leukocyte (PMN)). We describe a plasma-membrane associated ca. 55-kDa LPS-binding protein of human PMN that is indistinguishable from the bactericidal/permeability-increasing protein (BPI). To detect LPS-binding proteins on the cell surface, PMN were biotinylated before detergent solubilization and incubation with LPS-coated beads. Several biotinylated proteins bound to LPS-coated beads but not to uncoated beads and were characterized after elution with detergent by SDS-PAGE and western blotting using streptavidin-horseradish peroxidase. The spectrum of biotinylated proteins binding to and eluting from LPS-coated beads increased as the number of beads incubated with PMN lysate increased. However, at all concentrations of beads a 55-kDa protein was a dominant component of the eluate. Binding of the 55-kDa protein to LPS-coated beads was inhibited by lipid A, and both homologous and heterologous LPS, but not by peptidoglycan. Similar amounts of biotinylated 55-kDa LPS-binding protein were detected on PMN from patients with paroxysmal nocturnal hemoglobinuria who lacked membrane bound CD14, a known ca. 55-kDa plasma membrane-associated LPS-binding protein, indicating that the recovered biotinylated protein is not CD14. Several pieces of evidence, however, do indicate that the 55-kDa surface protein is BPI: 1) flow cytometry of PMN after labeling with rabbit anti-BPI serum and FITC-labeled goat anti-rabbit IgG revealed immunoreactive surface molecules on resting PMN and, in increased amounts, on PMN stimulated with FMLP or TNF; 2) This antiserum specifically and quantitatively inhibited binding of the biotinylated 55-kDa species to LPS-coated beads; 3) both BPI and the 55-kDa protein migrated as a doublet during SDS-PAGE and were both converted to single migrated species after N-glycosidase F treatment; 4) chemical cleavage of the biotinylated protein and native BPI with N-chlorosuccinimide yielded the same fragments. Thus, we have positively identified BPI as a LPS-binding protein on the surface of PMN. The role of this potent antibacterial, endotoxin neutralizing protein on the surface of PMN remains to be established.
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Wright, S. D., and M. T. Jong. "Adhesion-promoting receptors on human macrophages recognize Escherichia coli by binding to lipopolysaccharide." Journal of Experimental Medicine 164, no. 6 (December 1, 1986): 1876–88. http://dx.doi.org/10.1084/jem.164.6.1876.
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We report here that human macrophages bind Escherichia coli by recognizing bacterial lipopolysaccharide (LPS). Purified LPS was inserted into erythrocyte membranes, and the resulting LPS-coated red cells were bound by macrophages with the same temperature and cation dependence as observed for E. coli. When receptors for LPS were withdrawn from the plasma membrane by spreading the macrophages on LPS-coated surfaces, the binding of E. coli was blocked. We have also identified the receptors on macrophages that recognize LPS. Macrophages express three structurally homologous cell surface proteins, CR3, lymphocyte function-associated antigen (LFA-1), and p150,95. We used surface-bound monoclonal antireceptor antibodies to selectively remove these proteins from the apical surface of macrophages. We found that each of these proteins mediated the binding of E. coli to macrophages.
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Tobias, P. S., K. Soldau, L. Kline, J. D. Lee, K. Kato, T. P. Martin, and R. J. Ulevitch. "Cross-linking of lipopolysaccharide (LPS) to CD14 on THP-1 cells mediated by LPS-binding protein." Journal of Immunology 150, no. 7 (April 1, 1993): 3011–21. http://dx.doi.org/10.4049/jimmunol.150.7.3011.
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Abstract Recent work has established that bacterial endotoxin (LPS) binds to the plasma protein LPS-binding protein (LBP) forming high affinity complexes (LPS-LBP), that LBP is an opsonin for LPS-bearing particles, and that LPS-LBP complexes are potent agonists for monocytic cells (MO). mAb to the MO plasma membrane protein, CD14, inhibit LBP-dependent binding of LPS to MO, and LPS-LBP-dependent stimulation of cytokine release from MO. These data suggest that CD14 functions as a membrane receptor for LPS but do not demonstrate a direct association of LPS with CD14. Calcitriol was used to induce a high level of CD14 expression in the human monocyte-like cell line THP-1, resulting in enhanced responses of these cells to LPS-LBP complexes manifested by enhanced binding of LPS and a decrease in the amount of LPS needed to induce IL-8 release. An Re595 LPS derivative containing a radioiodinated, photoreactive, phenyl azide (125I-ASD-LPS) was used in cross-linking experiments to identify membrane proteins in calcitriol-treated THP-1 cells that interact with LPS. 125I-ASD-LPS was added to calcitriol-induced THP-1 cells in the presence or absence of LBP, the mixture photolyzed, and the resultant radioiodinated proteins analyzed by SDS-PAGE and autoradiography. We observed strong cross-linking of 125I-ASD-LPS to a 55-kDa membrane protein when LBP was present, but failed to observe radiolabeling of any other proteins with apparent molecular masses distinct from CD14. The cross-linked product was identified as CD14 by immunoprecipitation with anti-human CD14 mAb. Studies with human CD14 expressing transfectants of the murine B cell line 70Z/3 also revealed LBP-dependent cross-linking of 125I-ASD-LPS to CD14. These data document binding of LPS to a specific membrane protein that serves as an LPS receptor.
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Tobias, Peter S., Katrin Soldau, Nicole M. Iovine, Peter Elsbach, and Jerrold Weiss. "Lipopolysaccharide (LPS)-binding Proteins BPI and LBP Form Different Types of Complexes with LPS." Journal of Biological Chemistry 272, no. 30 (July 25, 1997): 18682–85. http://dx.doi.org/10.1074/jbc.272.30.18682.
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Dentener, M. A., E. J. Von Asmuth, G. J. Francot, M. N. Marra, and W. A. Buurman. "Antagonistic effects of lipopolysaccharide binding protein and bactericidal/permeability-increasing protein on lipopolysaccharide-induced cytokine release by mononuclear phagocytes. Competition for binding to lipopolysaccharide." Journal of Immunology 151, no. 8 (October 15, 1993): 4258–65. http://dx.doi.org/10.4049/jimmunol.151.8.4258.
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Abstract Serum proteins play an important role in LPS-induced cell activation. The LPS binding protein (LBP) enhances cellular responses to LPS, whereas the polymorphonuclear leukocyte product bactericidal/permeability-increasing protein (BPI) inhibits LPS-induced cell activation. In this study the influences of LBP and BPI, two proteins with opposite effects, but with considerable sequence homology, on LPS-induced mononuclear phagocytic cell cytokine release was studied. LBP was shown to enhance LPS-induced TNF-alpha, IL-6, and IL-8 release by mononuclear phagocytic cells, whereas BPI inhibited the release of these cytokines. Furthermore, the effects of LBP and BPI on LPS-induced cytokine release by mononuclear phagocytic cells were shown to be counteractive. BPI interfered with the enhancing effect of LBP on the LPS-induced cytokine release. At high LBP to BPI ratios, BPI could no longer inhibit LBP-induced enhancement. In accordance, increasing concentrations of BPI abrogated the LBP effect. Next, it was shown that LBP and BPI compete for binding to LPS by using an assay system that detects binding of free BPI to an anti-BPI mAb. LPS prevented binding of BPI to anti-BPI mAb, whereas preincubation of LPS with LBP prevented the LPS-induced inhibition. Also, it was observed that both BPI and LBP inhibited LPS activity in the chromogenic LAL assay. We conclude from this study that LBP and BPI have counteractive effects on LPS-induced mononuclear phagocytic cell cytokine release by competing for binding to LPS.
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Gravallese, E. M., J. M. Darling, L. H. Glimcher, and M. Boothby. "Role of lipopolysaccharide and IL-4 in control of transcription of the class II A alpha gene." Journal of Immunology 147, no. 7 (October 1, 1991): 2377–83. http://dx.doi.org/10.4049/jimmunol.147.7.2377.
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Abstract The class II (Ia) MHC molecules are cell surface proteins that regulate the activation of T cells. B lymphocyte expression of class II molecules has been shown to be influenced by a number of external stimuli. It has been previously demonstrated that treatment of these cells with IL-4 leads to an increase in class II gene transcription at 18 h as well as to an increase in steady state class II mRNA. It has also been previously demonstrated that LPS treatment of splenic B cells from athymic mice results in a decrease in steady state mRNA encoding the A alpha class II protein. This decrease persists for at least 18 h. Nuclear run-on transcription assays now demonstrate that although steady state mRNA levels for A alpha are decreased by LPS treatment of athymic mouse lymphocytes, LPS does not decrease A alpha gene transcription, but rather modestly activates transcription of this class II gene. LPS and IL-4 have been demonstrated to be synergistic stimuli for a number of genes. Costimulation of splenic lymphocytes from athymic mice with IL-4 plus LPS leads to activation of transcription, but the increase in transcription is no more than that seen with IL-4 stimulation alone. However, in costimulated lymphocytes, steady state A alpha-encoding mRNA levels are intermediate between the increased levels seen with IL-4 stimulation and the decreased levels seen with LPS stimulation. Therefore, LPS and IL-4 act nonsynergistically in class II gene transcription and the effects of LPS in decreasing steady state mRNA are most likely posttranscriptional. An IL-4-inducible and an LPS-inducible DNA-binding protein have been previously identified in splenic lymphocytes from athymic mice. Both nuclear binding proteins form complexes with the same DNA fragments from a control region of the A alpha gene. These nucleoprotein complexes comigrate under nondenaturing conditions and display identical patterns of binding with a panel of oligonucleotide competitors. Oligonucleotides representing protein binding sites of the IL-4 and LPS-induced DNA-binding proteins cross-compete for protein binding. Therefore, the binding proteins induced by LPS and IL-4 are likely related, and may function at different efficiencies as activators of A alpha gene transcription.
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Pulido, David, Rocío Rebollido-Rios, Javier Valle, David Andreu, Ester Boix, and Marc Torrent. "Structural similarities in the CPC clip motif explain peptide-binding promiscuity between glycosaminoglycans and lipopolysaccharides." Journal of The Royal Society Interface 14, no. 136 (November 2017): 20170423. http://dx.doi.org/10.1098/rsif.2017.0423.
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Lipopolysaccharides (LPSs) and glycosaminoglycans (GAGs) are polymeric structures containing negatively charged disaccharide units that bind to specialized proteins and peptides in the human body and control fundamental processes such as inflammation and coagulation. Surprisingly, some proteins can bind both LPSs and GAGs with high affinity, suggesting that a cross-communication between these two pathways can occur. Here, we explore whether GAGs and LPSs can share common binding sites in proteins and what are the structural determinants of this binding. We found that the LPS-binding peptide YI12WF, derived from protein FhuA, can bind both heparin and E. coli LPS with high affinity. Most interestingly, mutations decreasing heparin binding in the peptide also reduce LPS affinity. We show that such mutations involve the CPC clip motif in the peptide, a small three-dimensional signature required for heparin binding. Overall, we conclude that negatively charged polysaccharide-containing polymers such as GAGs and LPSs can compete for similar binding sites in proteins, and that the CPC clip motif is essential to bind both ligands. Our results provide a structural framework to explain why these polymers can cross-interact with the same proteins and peptides and thus contribute to the regulation of apparently unrelated processes in the body.
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Gravallese, E. M., M. R. Boothby, C. M. Smas, and L. H. Glimcher. "A lipopolysaccharide-induced DNA-binding protein for a class II gene in B cells is distinct from NF-kappa B." Molecular and Cellular Biology 9, no. 8 (August 1989): 3184–92. http://dx.doi.org/10.1128/mcb.9.8.3184-3192.1989.
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Class II (Ia) major histocompatibility complex molecules are cell surface proteins normally expressed by a limited subset of cells of the immune system. These molecules regulate the activation of T cells and are required for the presentation of antigens and the initiation of immune responses. The expression of Ia in B cells is determined by both the developmental stage of the B cell and by certain external stimuli. It has been demonstrated previously that treatment of B cells with lipopolysaccharide (LPS) results in increased surface expression of Ia protein. However, we have confirmed that LPS treatment results in a significant decrease in mRNA encoding the Ia proteins which persists for at least 18 h. Within the upstream regulatory region of A alpha k, an NF-kappa B-like binding site is present. We have identified an LPS-induced DNA-binding protein in extracts from athymic mice whose spleens consist predominantly of B cells. Binding activity is present in low levels in unstimulated spleen cells and is increased by LPS treatment. This protein binds to two sites in a regulatory region of the Ia A alpha k gene, one of which contains the NF-kappa B-like binding site. DNA fragments containing these sites cross-compete for protein binding. Analysis by DNase I footprinting identified a target binding sequence, named the LPS-responsive element. Although this target sequence contains an NF-kappa B-like binding site, competition with a mutant oligonucleotide demonstrated that bases critical for NF-kappa B binding are not required for binding of the LPS-inducible protein. Therefore, we hypothesized that this inducible protein represents a new mediator of LPS action, distinct from NF-kappa B, and may be one mechanism to account for the decrease in mRNA encoding the Ia proteins.
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Gravallese, E. M., M. R. Boothby, C. M. Smas, and L. H. Glimcher. "A lipopolysaccharide-induced DNA-binding protein for a class II gene in B cells is distinct from NF-kappa B." Molecular and Cellular Biology 9, no. 8 (August 1989): 3184–92. http://dx.doi.org/10.1128/mcb.9.8.3184.
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Class II (Ia) major histocompatibility complex molecules are cell surface proteins normally expressed by a limited subset of cells of the immune system. These molecules regulate the activation of T cells and are required for the presentation of antigens and the initiation of immune responses. The expression of Ia in B cells is determined by both the developmental stage of the B cell and by certain external stimuli. It has been demonstrated previously that treatment of B cells with lipopolysaccharide (LPS) results in increased surface expression of Ia protein. However, we have confirmed that LPS treatment results in a significant decrease in mRNA encoding the Ia proteins which persists for at least 18 h. Within the upstream regulatory region of A alpha k, an NF-kappa B-like binding site is present. We have identified an LPS-induced DNA-binding protein in extracts from athymic mice whose spleens consist predominantly of B cells. Binding activity is present in low levels in unstimulated spleen cells and is increased by LPS treatment. This protein binds to two sites in a regulatory region of the Ia A alpha k gene, one of which contains the NF-kappa B-like binding site. DNA fragments containing these sites cross-compete for protein binding. Analysis by DNase I footprinting identified a target binding sequence, named the LPS-responsive element. Although this target sequence contains an NF-kappa B-like binding site, competition with a mutant oligonucleotide demonstrated that bases critical for NF-kappa B binding are not required for binding of the LPS-inducible protein. Therefore, we hypothesized that this inducible protein represents a new mediator of LPS action, distinct from NF-kappa B, and may be one mechanism to account for the decrease in mRNA encoding the Ia proteins.
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Ding, A., E. Sanchez, M. Tancinco, and C. Nathan. "Interactions of bacterial lipopolysaccharide with microtubule proteins." Journal of Immunology 148, no. 9 (May 1, 1992): 2853–58. http://dx.doi.org/10.4049/jimmunol.148.9.2853.
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Abstract Bacterial LPS is a potent stimulator of immune cells, but its mechanisms are unknown. A possible role for microtubules in LPS actions has been indicated by previous findings that the microtubule-active agent, taxol, can mimic some effects of LPS in macrophages from normal strains of mice, but not from genetically LPS-hyporesponsive strains. In this report we demonstrate that isolated microtubules from mouse brain can bind LPS in vitro. LPS and tubulin coeluted through a gel filtration column, and LPS was cross-linked to microtubule proteins with an iodinatable, photoreactive agent, sulfosuccinimidyl 2-(p-azidosalicylamido) ethyl-1,3'-dithiopropionate. beta-Tubulin and microtubule-associated protein-2 (MAP), a predominant MAP in the brain, bound LPS specifically. Cross-linking was inhibited by an excess of unlabeled LPS or partially by unlabeled lipid A, but not by 2 M NaCl. Under the same conditions, neither myosin nor soybean trypsin inhibitor was labeled by the photoaffinity LPS probe, nor did these proteins compete for binding of LPS to beta-tubulin. These findings support the hypothesis that the microtubule network could be an intracellular target for LPS, and suggest further that a beta-tubulin-associated MAP could have an important role in LPS actions.
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EBERHARD, A. David, and R. Scott VANDENBERG. "Annexins I and II bind to lipid A: a possible role in the inhibition of endotoxins." Biochemical Journal 330, no. 1 (February 15, 1998): 67–72. http://dx.doi.org/10.1042/bj3300067.
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Annexins are Ca2+-dependent phospholipid-binding proteins with anti-inflammatory properties that are present on the surfaces of, and released from, certain cell types, such as leukocytes and secretory epithelia. The present study investigated the possibility that annexins may bind directly to bacterial endotoxin, inhibiting its interactions with cellular receptors or accessory binding proteins. An enzyme-linked immunoassay demonstrated calcium-dependent binding of low nanomolar concentrations of annexin-I and annexin-II p36/p11 heterotetramer to lipid A. In contrast, little or no annexin binding to lipopolysaccharide (LPS) was detected under similar conditions. LPS-binding protein binding to lipid A was blocked by annexin-I, and the annexins inhibited nitrite generation in RAW 264.7 cells induced by lipid A but not that induced by LPS. The data suggest that direct binding of annexins to lipid A may represent a mechanism for suppressing cellular and systemic responses to endotoxin.
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Krasity, Benjamin C., Joshua V. Troll, Jerrold P. Weiss, and Margaret J. McFall-Ngai. "LBP/BPI proteins and their relatives: conservation over evolution and roles in mutualism." Biochemical Society Transactions 39, no. 4 (July 20, 2011): 1039–44. http://dx.doi.org/10.1042/bst0391039.
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LBP [LPS (lipopolysaccharide)-binding protein] and BPI (bactericidal/permeability-increasing protein) are components of the immune system that have been principally studied in mammals for their involvement in defence against bacterial pathogens. These proteins share a basic architecture and residues involved in LPS binding. Putative orthologues, i.e. proteins encoded by similar genes that diverged from a common ancestor, have been found in a number of non-mammalian vertebrate species and several non-vertebrates. Similar to other aspects of immunity, such as the activity of Toll-like receptors and NOD (nucleotide-binding oligomerization domain) proteins, analysis of the conservation of LBPs and BPIs in the invertebrates promises to provide insight into features essential to the form and function of these molecules. This review considers state-of-the-art knowledge in the diversity of the LBP/BPI proteins across the eukaryotes and also considers their role in mutualistic symbioses. Recent studies of the LBPs and BPIs in an invertebrate model of beneficial associations, the Hawaiian bobtail squid Euprymna scolopes' alliance with the marine luminous bacterium Vibrio fischeri, are discussed as an example of the use of non-vertebrate models for the study of LBPs and BPIs.
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Triyatni, Miriam, Bertrand Saunier, Padma Maruvada, Anthony R. Davis, Luca Ulianich, Theo Heller, Arvind Patel, Leonard D. Kohn, and T. Jake Liang. "Interaction of Hepatitis C Virus-Like Particles and Cells: a Model System for Studying Viral Binding and Entry." Journal of Virology 76, no. 18 (September 15, 2002): 9335–44. http://dx.doi.org/10.1128/jvi.76.18.9335-9344.2002.
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ABSTRACT Hepatitis C virus-like particles (HCV-LPs) containing the structural proteins of HCV H77 strain (1a genotype) was used as a model for HCV virion to study virus-cell interaction. HCV-LPs showed a buoyant density of 1.17 to 1.22 g/cm3 in a sucrose gradient and formed double-shelled particles 35 to 49 nm in diameter. Flow cytometry analysis by an indirect method (detection with anti-E2 antibody) and a direct method (use of dye-labeled HCV-LPs) showed that HCV-LPs binds to several human hepatic (primary hepatocytes, HepG2, HuH7, and NKNT-3) and T-cell (Molt-4) lines. HCV-LPs binding to cells occurred in a dose- and calcium-dependent manner and was not mediated by CD81. Scatchard plot analysis suggests the presence of two binding sites for HCV-LPs with high (Kd ∼1 μg/ml) and low (Kd ∼50 to 60 μg/ml) affinities of binding. Anti-E1 and -E2 antibodies inhibited HCV-LPs binding to cells. While preincubation of HCV-LPs with very-low-density lipoprotein (VLDL), low-density lipoprotein (LDL), or high-density lipoprotein (HDL) blocked its binding to cells, preincubation of cells with VLDL, LDL, HDL, or anti-LDL-R antibody did not. Confocal microscopy analysis showed that, after binding to cells, dye-labeled HCV-LPs were internalized into the cytoplasm. This process could be inhibited with anti-E1 or anti-E2 antibodies, suggesting that E1 and E2 proteins mediate HCV-LPs binding and, subsequently, their entry into cells. Altogether, our results indicate that HCV-LPs can be used to further characterize the mechanisms involved in the early steps of HCV infection.
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Youn, Ju Ho, and Jeon-Soo Shin. "Identification of lipopolysaccharide binding site on High Mobility Group Box 1 Protein (98.23)." Journal of Immunology 182, no. 1_Supplement (April 1, 2009): 98.23. http://dx.doi.org/10.4049/jimmunol.182.supp.98.23.
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Abstract Lipopolysaccharide (LPS), a bacterial endotoxin, triggers deleterious systemic inflammatory responses when released into blood circulation, causing severe sepsis, organ dysfunction and death. LPS binding components in serum play an important role in modifying LPS toxicity by facilitating its interaction with the LPS signaling receptor, which is expressed on LPS-responsive cells. We have previously shown that HMGB1 is able to bind LPS and this binding can increase LPS-induced TNF-α production in human peripheral blood monocytes. In this report, we identified several LPS binding regions within human HMGB1 sequence by pull-down experiments with synthetic biotinylated peptide derived from HMGB1. Using a conventional sequence-based comparison with several other LPS-binding proteins, we identified similar LPS-binding motifs in LPS-binding peptides from HMGB1, but inhibition assay demonstrated that the capacity of these peptides to interfere with LPS-HMGB1 interaction exhibits different characteristics We are now carrying out further experiments to evaluate which amino acid residues contribute to LPS binding and functional differences between different peptide in LPS-binding capacities. Our studies identified a defined region of HMGB1 involved in LPS binding, thereby implicating a physiological role of human HMGB1 as an LPS-binding protein. [This study was supported by a grant from the Korean Health 21 R&D Project, Ministry of Health & Welfare, Republic of Korea (A080694) and Brain Korea 21 project to Medical Science.]
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Beamer, Lesa J., Daniel Fischer, and David Eisenberg. "Detecting distant relatives of mammalian LPS-binding and lipid transport proteins." Protein Science 7, no. 7 (July 1998): 1643–46. http://dx.doi.org/10.1002/pro.5560070721.
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Bhat, Nayantara, Pin-Yu Perera, Joan M. Carboni, Jorge Blanco, Douglas T. Golenbock, Tanya N. Mayadas, and Stefanie N. Vogel. "Use of a Photoactivatable Taxol Analogue to Identify Unique Cellular Targets in Murine Macrophages: Identification of Murine CD18 as a Major Taxol-Binding Protein and a Role for Mac-1 in Taxol-Induced Gene Expression." Journal of Immunology 162, no. 12 (June 15, 1999): 7335–42. http://dx.doi.org/10.4049/jimmunol.162.12.7335.
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Abstract Taxol, a potent antitumor agent that binds β-tubulin and promotes microtubule assembly, results in mitotic arrest at the G2/M phase of the cell cycle. More recently, Taxol was shown to be a potent LPS mimetic in murine, but not in human macrophages, stimulating signaling pathways and gene expression indistinguishably from LPS. Although structurally unrelated to LPS, Taxol’s LPS-mimetic activities are blocked by inactive structural analogues of LPS, indicating that despite the species-restricted effects of Taxol, LPS and Taxol share a common receptor/signaling complex that might be important in LPS-induced human diseases. To identify components of the putatively shared Taxol/LPS receptor, a novel, photoactivatable Taxol analogue was employed to identify unique Taxol-binding proteins in murine macrophage membranes. Seven major Taxol-binding proteins, ranging from ∼50 to 200 kDa, were detected. Although photoactivatable Taxol analogue failed to bind to CD14, the prominent Taxol-binding protein was identified as CD18, the ∼96-kDa common component of the β2 integrin family. This finding was supported by the concomitant failure of macrophage membranes from Mac-1 knockout mice to express immunoreactive CD18 and the major Taxol-binding protein. In addition, Taxol-induced IL-12 p40 mRNA was markedly reduced in Mac-1 knockout macrophages and anti-Mac-1 Ab blocked secretion of IL-12 p70 in Taxol- and LPS-stimulated macrophages. Since CD18 has been described as a participant in LPS-induced binding and signal transduction, these data support the hypothesis that the interaction of murine CD18 with Taxol is involved in its proinflammatory activity.
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Wellnitz, Sabine, Bettina Klumpp, Heidi Barth, Susumu Ito, Erik Depla, Jean Dubuisson, Hubert E. Blum, and Thomas F. Baumert. "Binding of Hepatitis C Virus-Like Particles Derived from Infectious Clone H77C to Defined Human Cell Lines." Journal of Virology 76, no. 3 (February 1, 2002): 1181–93. http://dx.doi.org/10.1128/jvi.76.3.1181-1193.2002.
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ABSTRACT Hepatitis C virus (HCV) is a leading cause of chronic hepatitis in the world. The study of viral entry and infection has been hampered by the inability to efficiently propagate the virus in cultured cells and the lack of a small-animal model. Recent studies have shown that in insect cells, the HCV structural proteins assemble into HCV-like particles (HCV-LPs) with morphological, biophysical, and antigenic properties similar to those of putative virions isolated from HCV-infected humans. In this study, we used HCV-LPs derived from infectious clone H77C as a tool to examine virus-cell interactions. The binding of partially purified particles to human cell lines was analyzed by fluorescence-activated cell sorting with defined monoclonal antibodies to envelope glycoprotein E2. HCV-LPs demonstrated dose-dependent and saturable binding to defined human lymphoma and hepatoma cell lines but not to mouse cell lines. Binding could be inhibited by monoclonal anti-E2 antibodies, indicating that the HCV-LP-cell interaction was mediated by envelope glycoprotein E2. Binding appeared to be CD81 independent and did not correlate with low-density lipoprotein receptor expression. Heat denaturation of HCV-LPs drastically reduced binding, indicating that the interaction of HCV-LPs with target cells was dependent on the proper conformation of the particles. In conclusion, our data demonstrate that insect cell-derived HCV-LPs bind specifically to defined human cell lines. Since the envelope proteins of HCV-LPs are presumably presented in a virion-like conformation, the binding of HCV-LPs to target cells may allow the study of virus-host cell interactions, including the isolation of HCV receptor candidates and antibody-mediated neutralization of binding.
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Vesy, C. J., R. L. Kitchens, G. Wolfbauer, J. J. Albers, and R. S. Munford. "Lipopolysaccharide-Binding Protein and Phospholipid Transfer Protein Release Lipopolysaccharides from Gram-Negative Bacterial Membranes." Infection and Immunity 68, no. 5 (May 1, 2000): 2410–17. http://dx.doi.org/10.1128/iai.68.5.2410-2417.2000.
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ABSTRACT Although animals mobilize their innate defenses against gram-negative bacteria when they sense the lipid A moiety of bacterial lipopolysaccharide (LPS), excessive responses to this conserved bacterial molecule can be harmful. Of the known ways for decreasing the stimulatory potency of LPS in blood, the binding and neutralization of LPS by plasma lipoproteins is most prominent. The mechanisms by which host lipoproteins take up the native LPS that is found in bacterial membranes are poorly understood, however, since almost all studies of host-LPS interactions have used purified LPS aggregates. Using nativeSalmonella enterica serovar Typhimurium outer membrane fragments (blebs) that contained 3H-labeled lipopolysaccharide (LPS) and 35S-labeled protein, we found that two human plasma proteins, LPS-binding protein (LBP) and phospholipid transfer protein (PLTP), can extract [3H]LPS from bacterial membranes and transfer it to human high-density lipoproteins (HDL). Soluble CD14 (sCD14) did not release LPS from blebs yet could facilitate LBP-mediated LPS transfer to HDL. LBP, but not PLTP, also promoted the activation of human monocytes by bleb-derived LPS. Whereas depleting or neutralizing LBP significantly reduced LPS transfer from blebs to lipoproteins in normal human serum, neutralizing serum PLTP had no demonstrable effect. Of the known lipid transfer proteins, LBP is thus most able to transfer LPS from bacterial membranes to the lipoproteins in normal human serum.
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Lin, Shih-Chang, Henry H. Wortis, and Janet Stavnezer. "The Ability of CD40L, but Not Lipopolysaccharide, To Initiate Immunoglobulin Switching to Immunoglobulin G1 Is Explained by Differential Induction of NF-κB/Rel Proteins." Molecular and Cellular Biology 18, no. 9 (September 1, 1998): 5523–32. http://dx.doi.org/10.1128/mcb.18.9.5523.
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ABSTRACT Antibodies of the immunoglobulin G1 class are induced in mice by T-cell-dependent antigens but not by lipopolysaccharide (LPS). CD40 engagement contributes to this preferential isotype production by activating NF-κB/Rel to induce germ line γ1 transcripts, which are essential for class switch recombination. Although LPS also activates NF-κB, it poorly induces germ line γ1 transcripts. Western blot analyses show that CD40 ligand (CD40L) induces all NF-κB/Rel proteins, whereas LPS activates predominantly p50 and c-Rel. Electrophoretic mobility shift assays show that in CD40L-treated cells, p50-RelA and p50-RelB dimers are the major NF-κB complexes binding to the germ line γ1 promoter, whereas in LPS-treated cells, p50–c-Rel and p50-p50 dimers are the major binding complexes. Transfection of expression plasmids for NF-κB/Rel fusion proteins (forced dimers) indicates that p50-RelA and p50-RelB dimers activate the germ line γ1 promoter and that p50–c-Rel and p50-p50 dimers inhibit this activation by competitively binding to the promoter without activating the promoter. Therefore, germ line γ1 transcription depends on the composition of NF-κB/Rel proteins.
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Rabinovich-Ernst, Orna, Clinton Bradfield, SungHwan Yoon, Anthony Armstrong, Samuel Katz, Aleksandra Nita-Lazar, and Iain Fraser. "TurboID biotin-tagging mass spectrometry identifies specific caspase-11-associated proteins regulating non-canonical inflammasome activation." Journal of Immunology 206, no. 1_Supplement (May 1, 2021): 15.06. http://dx.doi.org/10.4049/jimmunol.206.supp.15.06.
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Abstract While it has been demonstrated that cytosolic LPS can directly activate caspase11, the cellular processes regulating the non-canonical inflammasome response remain poorly defined. Caspase11 and caspase1 show substantial structural similarity, however, unlike the activation of caspase1 by NLR inflammasomes, there are no sensor or adaptor proteins known to be involved in transmitting cytosolic LPS signal to caspase11. Also, while caspase11 has been shown to associate with LPS, it lacks a characteristic LPS binding domain as observed in many other LPS binding proteins such as MD2 and LBP. Thus, we hypothesized that other effectors may be required to facilitate cytosolic LPS recognition. Moreover, the pathway is likely to be tightly regulated as caspase11 activation leads to highly inflammatory cell death. To identify novel regulators of caspase11, we generated immortalized macrophages expressing a caspase11-TurboID-DHFR chimeric protein. The destabilizing domain was included to avoid cell death induced by caspase11 over-expression. We used a TurboID biotin-tagging MS assay to detect proteins in close proximity to caspase11 pre and post cytosolic LPS introduction. Importantly, the TurboID assay permits recognition of transient interactions, typically missed by traditional IP. To validate relevance of putative hits, we used siRNA knockdown in BMDM. We’ve identified novel regulators specific for cytosolic LPS triggering. Several proteins interact with caspase11 only in the resting state, suggesting negative regulation to prevent pyroptosis. Among the identified regulators are kinases and proteins with pyrin and LRR domains, both common NLR features. This work was supported by the Intramural Research Program of NIAID, NIH.
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Koraha, Jun, Naoko Tsuneyoshi, Masao Kimoto, Jean-Francois Gauchat, Hiroshi Nakatake, and Kenji Fukudome. "Comparison of Lipopolysaccharide-Binding Functions of CD14 and MD-2." Clinical Diagnostic Laboratory Immunology 12, no. 11 (November 2005): 1292–97. http://dx.doi.org/10.1128/cdli.12.11.1292-1297.2005.
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ABSTRACT Prior to being recognized by the cell surface Toll-like receptor 4/MD-2 complex, lipopolysaccharide (LPS) in the bacterial outer membrane has to be processed by LPS-binding protein and CD14. CD14 forms a complex with monomeric LPS extracted by LPS-binding protein and transfers LPS to the cell surface signaling complex. In a previous study, we prepared a functional recombinant MD-2 using a bacterial expression system. We expressed the recombinant protein in Escherichia coli as a fusion protein with thioredoxin and demonstrated specific binding to LPS. In this study, we prepared recombinant CD14 fusion proteins using the same approach. Specific binding of LPS was demonstrated with a recombinant protein containing 151 amino-terminal residues. The region contained a hydrophilic region and the first three leucine-rich repeats (LRRs). The LRRs appeared to contribute to the binding because removal of the region resulted in a reduction in the binding function. LPS binding to the recombinant MD-2 was resistant to detergents. On the other hand, the binding to CD14 was prevented in the presence of low concentrations of detergents. In the case of human MD-2, the secondary myristoyl chain of LPS added by LpxM was required for the binding. A nonpathogenic penta-acyl LPS mutant lacking the myristoyl chain did not bind to MD-2 but did so normally to CD14. The broader LPS-binding spectrum of CD14 may allow recognition of multiple pathogens, and the lower affinity for LPS binding of CD14 allows transmission of captured materials to MD-2.
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Ghafouri, B., E. Kihlström, B. Ståhlbom, C. Tagesson, and M. Lindahl. "PLUNC (palate, lung and nasal epithelial clone) proteins in human nasal lavage fluid." Biochemical Society Transactions 31, no. 4 (August 1, 2003): 810–14. http://dx.doi.org/10.1042/bst0310810.
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PLUNC (palate, lung and nasal epithelial clone) is a newly discovered gene that is expressed in the upper respiratory tract and is suggested to be of importance in host defence against bacteria. We have identified two forms of the PLUNC protein in human nasal lavage fluid (NLF) using two-dimensional gel electrophoresis (2-DE) and MS. The apparent molecular masses and isoelectric points of these forms are 24.8 kDa/pI 5.4 and 25.1 kDa/pI 5.5. Notably, the 24.8 kDa/pI 5.4 form of PLUNC is an abundant protein in the 2-DE protein patterns of NLF from healthy subjects. Decreased levels of PLUNC were found in NLF from smokers and workers exposed to reactive epoxy chemicals, indicating that long-term exposure to airway irritants impairs the production of PLUNC in the upper respiratory tract. We have also investigated the presence of lipopolysaccharide (LPS)-binding proteins in NLF. Five proteins were found to adsorb to a LPS-coated surface; two of these proteins correspond to the two PLUNC forms, as judged by 2-DE pattern matching. For comparison, human saliva was found to contain a set of LPS-binding proteins with similar 2-DE spot positions (the same pIs but somewhat lower apparent molecular masses of ≈20 kDa). These results indicate that PLUNC may be a new marker of airway inflammation and may play a part in the innate immune response, and that human saliva contains yet other members of the family of LPS-binding proteins.
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Roth, Robert I. "Hemoglobin Enhances the Binding of Bacterial Endotoxin to Human Endothelial Cells." Thrombosis and Haemostasis 76, no. 02 (1996): 258–62. http://dx.doi.org/10.1055/s-0038-1650565.
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SummaryHuman endothelial cells, when incubated with bacterial endotoxin (lipopolysaccharide, LPS), modify their surface in association with prominent production of procoagulant tissue factor (TF) activity. This deleterious biological effect of LPS has been shown previously to be enhanced approximately 10-fold by the presence of hemoglobin (Hb), a recently recognized LPS binding protein that causes disaggregation of LPS and increases the biological activity of LPS in a number of in vitro assays. The present study was performed to test the hypothesis that Hb enhances the LPS-induced procoagulant activity of human umbilical vein endothelial cells (HUVEC) by increasing LPS binding to the cells. The binding of 3H-LPS to HUVEC was determined in the absence or presence of Hb or two other known LPS-binding proteins, human serum albumin (HSA) and IgG. LPS binding was substantially increased in the presence of Hb, in a Hb concentration-dependent manner, but was not increased by HSA or IgG. Hb enhancement of LPS binding was observed in serum-free medium, indicating that there was no additional requirement for any of the serum factors known to participate in the interaction of LPS with cells (e.g., lipopolysaccharide (LPS)-binding protein (LBP) and soluble CD14 (sCD14)). Hb enhancement of LPS binding also was observed in the more physiologic condition of 100% plasma. LPS-induced TF activity was stimulated by Hb, but not by HSA or IgG. In serum-free medium, TF activity was not stimulated under any of the conditions tested. Ultrafiltration of LPS was dramatically increased after incubation with Hb but not with HSA or IgG, suggesting that LPS disaggregation by Hb was responsible for the enhanced binding of LPS to HUVEC and the subsequent stimulation of TF activity.
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Zarewych, D. M., A. L. Kindzelskii, R. F. Todd, and H. R. Petty. "LPS induces CD14 association with complement receptor type 3, which is reversed by neutrophil adhesion." Journal of Immunology 156, no. 2 (January 15, 1996): 430–33. http://dx.doi.org/10.4049/jimmunol.156.2.430.
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Abstract CD14, a glycosylphosphatidyl inositol (GPI)-linked membrane protein, is a key membrane binding site for LPS (endotoxin). Although CD14 lacks transmembrane and cytoplasmic sequences, it activates CR3-mediated leukocyte adhesion and cytokine release. Since CR3 has been shown to interact with other GPI-linked membrane proteins, we tested the hypothesis that CD14 can physically associate with CR3. Using qualitative and quantitative resonance energy transfer microscopy, we show that LPS in the presence of serum or LPS binding protein triggers formation of CD14-CR3 complexes. Kinetic studies show that CD14-CR3 complexes dissociate as neutrophils attach to substrates. We speculate that LPS-charged CD14 enhances CR3-mediated adhesion by directly binding to CR3.
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de Haas, Carla J. C., Marijke E. van der Tol, Kok P. M. Van Kessel, Jan Verhoef, and Jos A. G. Van Strijp. "A Synthetic Lipopolysaccharide-Binding Peptide Based on Amino Acids 27–39 of Serum Amyloid P Component Inhibits Lipopolysaccharide-Induced Responses in Human Blood." Journal of Immunology 161, no. 7 (October 1, 1998): 3607–15. http://dx.doi.org/10.4049/jimmunol.161.7.3607.
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Abstract LPS-binding proteins in plasma play an important role in modifying LPS toxicity. Significant properties have already been attributed to the LPS-binding protein (LBP). It accelerates LPS toxicity as well as incorporation into high-density lipoproteins, leading to neutralization of LPS in serum. A search for other LPS-binding components in serum, using LPS-coated magnetic beads, revealed a new LPS-binding protein. N-terminal microsequencing identified this protein as serum amyloid P component (SAP). Purified SAP bound to smooth and rough types of LPS via the lipid A part. SAP inhibited the binding of FITC-labeled ReLPS (LPS from Salmonella minnesota strain R595) to human monocytes and the ReLPS-induced priming of the oxidative burst of human neutrophils only in the presence of low concentrations of LBP. In search for the LPS binding site of SAP, we found that pep27–39, a 13-mer peptide consisting of amino acids 27–39 of SAP, competitively inhibited the binding of LPS to SAP. In addition, pep27–39 significantly inhibited ReLPS-induced responses in phagocytes in the presence of serum, as well as in human whole blood. Carboxamidomethylated pep27–39 showed an even more pronounced reduction of the ReLPS-induced priming of phagocytes in human blood. Performing gel filtration of FITC-labeled ReLPS incubated with soluble CD14, we showed that SAP could not prevent binding of LPS to soluble CD14, in contrast to pep27–39. The ability of pep27–39 to antagonize specifically the effects of LPS in the complex environment of human blood suggests that pep27–39 may be a novel therapeutic agent in the treatment of Gram-negative sepsis.
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An, M. R., C. C. Hsieh, P. D. Reisner, J. P. Rabek, S. G. Scott, D. T. Kuninger, and J. Papaconstantinou. "Evidence for posttranscriptional regulation of C/EBPalpha and C/EBPbeta isoform expression during the lipopolysaccharide-mediated acute-phase response." Molecular and Cellular Biology 16, no. 5 (May 1996): 2295–306. http://dx.doi.org/10.1128/mcb.16.5.2295.
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The mRNAs of the CCAAT/enhancer-binding trans-activator proteins (C/EBPalpha and C/EBPbeta) serve as templates for the differential translation of several isoforms which have specific transcriptional regulatory functions. By using an oligonucleotide corresponding to the C/EBP binding site of the mouse alpha1-acid glycoprotein promoter, we detected multiple forms of C/EBPalpha and C/EBP++ beta proteins in the mouse liver that have DNA-binding activity. By using specific antisera, we detected C/EBPalphas with molecular masses of 42, 38, 30, and 20 kDa that have DNA-binding activity. The pool levels of the 42- and 30-kDa isoforms were high in control nuclear extracts and decreased significantly after lipopolysaccharide (LPS) treatment. The binding activity and protein levels of the 20-kDa isoform are low in controls and increase dramatically after LPS treatment. C/EBPbeta isoforms with molecular masses of 35, 20, and 16 kDa were also detected. The 35-kDa pool level did not change whereas the 20-kDa isoform was strongly induced in response to LPS. Western (immunoblot) and Southwestern (DNA-protein) analyses show that p42 C/EBPalpha forms specific complexes with the alpha1-acid glycoprotein oligonucleotide in control nuclear extract and that p20 C/EBP beta forms complexes in LPS-treated liver. Our studies suggest that synthesis of specific C/EBPalpha and C/EBPbeta isoforms occurred in the normal liver in vivo and that LPS mediated a differential initiation and inhibition of translation at specific AUG sites within each mRNA. The qualitative and quantitative changes in C/EBPalpha and C/EBPbeta isoform pool levels suggest that LPS or an LPS-stimulated factor can regulate the selection of AUG start sites for both activation and repression of translation. This regulation appears to involve an LPS-mediated down-regulation of initiation at the first AUG codon of the 42-kDa C/EBPalpha and dramatic translational up-regulation at the fifth AUG codon of the 20-kDa C/EBPalpha and the third AUG codon of the 20-kDa C/EBPbeta. These regulatory events suggest the existence of proteins that may act as translational trans-acting factors.
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Han, Ji, Yong Lee, Jun Im, Young Ham, Hee Lee, Sang Han, and Jin Hong. "Astaxanthin Ameliorates Lipopolysaccharide-Induced Neuroinflammation, Oxidative Stress and Memory Dysfunction through Inactivation of the Signal Transducer and Activator of Transcription 3 Pathway." Marine Drugs 17, no. 2 (February 18, 2019): 123. http://dx.doi.org/10.3390/md17020123.
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Astaxanthin (AXT), a xanthophyll carotenoid compound, has potent antioxidant, anti-inflammatory and neuroprotective properties. Neuroinflammation and oxidative stress are significant in the pathogenesis and development of Alzheimer’s disease (AD). Here, we studied whether AXT could alleviate neuroinflammation, oxidative stress and memory loss in lipopolysaccharide (LPS) administered mice model. Additionally, we investigated the anti-oxidant activity and the anti-neuroinflammatory response of AXT in LPS-treated BV-2 microglial cells. The AXT administration ameliorated LPS-induced memory loss. This effect was associated with the reduction of LPS-induced expression of inflammatory proteins, as well as the production of reactive oxygen species (ROS), nitric oxide (NO), cytokines and chemokines both in vivo and in vitro. AXT also reduced LPS-induced β-secretase and Aβ1–42 generation through the down-regulation of amyloidogenic proteins both in vivo and in vitro. Furthermore, AXT suppressed the DNA binding activities of the signal transducer and activator of transcription 3 (STAT3). We found that AXT directly bound to the DNA- binding domain (DBD) and linker domain (LD) domains of STAT3 using docking studies. The oxidative stress and inflammatory responses were not downregulated in BV-2 cells transfected with DBD-null STAT3 and LD-null STAT3. These results indicated AXT inhibits LPS-induced oxidant activity, neuroinflammatory response and amyloidogenesis via the blocking of STAT3 activity through direct binding.
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Chiba, Hirofumi, Hitomi Sano, Daisuke Iwaki, Seiji Murakami, Hiroaki Mitsuzawa, Toru Takahashi, Masanori Konishi, Hiroki Takahashi, and Yoshio Kuroki. "Rat Mannose-Binding Protein A Binds CD14." Infection and Immunity 69, no. 3 (March 1, 2001): 1587–92. http://dx.doi.org/10.1128/iai.69.3.1587-1592.2001.
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ABSTRACT Lipopolysaccharide (LPS) has been known to induce inflammation by interacting with CD14, which serves as a receptor for LPS. Mannose-binding protein (MBP) belongs to the collectin subgroup of the C-type lectin superfamily, along with surfactant proteins SP-A and SP-D. We have recently demonstrated that SP-A modulates LPS-induced cellular responses by interaction with CD14 (H. Sano, H. Sohma, T. Muta, S. Nomura, D. R. Voelker, and Y. Kuroki, J. Immunol. 163:387–395, 2000) and that SP-D also interacts with CD14 (H. Sano, H. Chiba, D. Iwaki, H. Sohma, D. R. Voelker, and Y. Kuroki, J. Biol. Chem. 275:22442–22451, 2000). In this study, we examined whether MBP, a collectin highly homologous to SP-A and SP-D, could bind CD14. Recombinant rat MBP-A bound recombinant human soluble CD14 in a concentration-dependent manner. Its binding was not inhibited in the presence of excess mannose or EDTA. MBP-A bound deglycosylated CD14 treated with N-glycosidase F, neuraminidase, and O-glycosidase, indicating that MBP-A interacts with the peptide portion of CD14. Since LPS was also a ligand for the collectins, we compared the characteristics of binding of MBP-A to LPS with those of binding to CD14. MBP-A bound to lipid A fromSalmonella enterica serovar Minnesota and rough LPS (S. enterica serovar Minnesota Re595 and Escherichia coli J5, Rc), but not to smooth LPS (E. coli O26:B6 and O111:B4). Unlike CD14 binding, EDTA and excess mannose attenuated the binding of MBP-A to rough LPS. From these results, we conclude that CD14 is a novel ligand for MBP-A and that MBP-A utilizes a different mechanism for CD14 recognition from that for LPS.
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MALHOTRA, Rajneesh, Richard PRIEST, and Michael I. BIRD. "Role for L-selectin in lipopolysaccharide-induced activation of neutrophils." Biochemical Journal 320, no. 2 (December 1, 1996): 589–93. http://dx.doi.org/10.1042/bj3200589.
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The activation of leucocytes by bacterial cell wall lipopolysaccharide (LPS) contributes to the pathogenesis of septic shock. LPS is known to interact with several cell-surface proteins, including CD14, when presented as a complex with serum LPS-binding protein. However, the identity of the receptor responsible for LPS signalling and leucocyte activation is unknown. Interestingly, mice deficient in cell-surface L-selectin were dramatically resistant to the lethal effects of high doses of LPS in a model of septic shock. Recently we reported that L-selectin binds to cardiolipin and other charged phospholipids at a site distinct from the carbohydrate-binding site. Structural similarities between charged phospholipids and the lipid A moiety of LPS prompted us to investigate interactions between L-selectin and LPS. Herein we show that L-selectin is a neutrophil surface receptor for LPS and lipotechoic acid. The binding of LPS to L-selectin is independent of serum and Ca2+, and is blocked by antibodies to L-selectin and fucoidan. Furthermore, the interaction of LPS with cell-surface L-selectin results in superoxide production, indicating that L-selectin can mediate both binding and activation of human neutrophils. These findings suggest novel therapeutic approaches for the treatment of septic shock.
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Cowan, Douglas B., Dimitrios N. Poutias, Pedro J. Del Nido, and Francis X. McGowan. "CD14-independent activation of cardiomyocyte signal transduction by bacterial endotoxin." American Journal of Physiology-Heart and Circulatory Physiology 279, no. 2 (August 1, 2000): H619—H629. http://dx.doi.org/10.1152/ajpheart.2000.279.2.h619.
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In the heart, lipopolysaccharide (LPS) induces the production of proinflammatory cytokines that cause myocardial dysfunction; however, the signaling pathways involved in cardiomyocyte responses are poorly understood. We studied LPS-induced signaling by treating cardiomyocyte cultures with 0.01–10 μg/ml LPS for 0–24 h in the presence or absence of 2.5% serum. Cytosolic and nuclear proteins were analyzed for expression and activation of protein kinases. Members of the extracellular signal-regulated kinase (ERK) and signal transducer and activators of transcription (STAT) protein families were uniformly expressed and specifically phosphorylated in response to LPS. Activation was biphasic; peaking at 5–10 min and 24 h after treatment. Inhibitor experiments provided evidence that ERK proteins may regulate STAT activity. Serum did not augment endotoxin-induced phosphorylation. Although cardiomyocytes expressed low levels of CD14 and LPS-binding protein, specific enzymatic removal of glycosyl phosphatidylinositol-linked receptors or incubation with an anti-CD14 antibody had no effect on kinase activation. Treatment of cells with an excess of detoxified LPS attenuated endotoxin-induced signaling. In addition, endotoxin stimulated specific binding of nuclear factors to AP-1, nuclear factor-κB (NF-κB), STAT1 (SIE, sis-inducible element), and STAT3 consensus-binding sequences. Finally, inhibition of ERK phosphorylation reduced, and NF-κB nuclear translocation prevented, tumor necrosis factor-α production. Our results indicate that LPS-induced activation of signal transduction in cardiomyocytes occurs by a CD14-independent mechanism.
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Gutsmann, Thomas, Iosu Razquin-Olazarán, Ina Kowalski, Yani Kaconis, Jörg Howe, Rainer Bartels, Mathias Hornef, et al. "New Antiseptic Peptides To Protect against Endotoxin-Mediated Shock." Antimicrobial Agents and Chemotherapy 54, no. 9 (July 6, 2010): 3817–24. http://dx.doi.org/10.1128/aac.00534-10.
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ABSTRACT Systemic bacterial infections are associated with high mortality. The access of bacteria or constituents thereof to systemic circulation induces the massive release of immunomodulatory mediators, ultimately causing tissue hypoperfusion and multiple-organ failure despite adequate antibiotic treatment. Lipid A, the “endotoxic principle” of bacterial lipopolysaccharide (LPS), is one of the major bacterial immunostimuli. Here we demonstrate the biological efficacy of rationally designed new synthetic antilipopolysaccharide peptides (SALPs) based on the Limulus anti-LPS factor for systemic application. We show efficient inhibition of LPS-induced cytokine release and protection from lethal septic shock in vivo, whereas cytotoxicity was not observed under physiologically relevant conditions and concentrations. The molecular mechanism of LPS neutralization was elucidated by biophysical techniques. The lipid A part of LPS is converted from its “endotoxic conformation,” the cubic aggregate structure, into an inactive multilamellar structure, and the binding affinity of the peptide to LPS exceeds those of known LPS-binding proteins, such as LPS-binding protein (LBP). Our results thus delineate a novel therapeutic strategy for the clinical management of patients with septic shock.
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Pilla, D. M., J. A. Hagar, A. K. Haldar, A. K. Mason, D. Degrandi, K. Pfeffer, R. K. Ernst, M. Yamamoto, E. A. Miao, and J. Coers. "Guanylate binding proteins promote caspase-11-dependent pyroptosis in response to cytoplasmic LPS." Proceedings of the National Academy of Sciences 111, no. 16 (April 8, 2014): 6046–51. http://dx.doi.org/10.1073/pnas.1321700111.
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Phillips, JD, DV Kinikini, Y. Yu, B. Guo, and EA Leibold. "Differential regulation of IRP1 and IRP2 by nitric oxide in rat hepatoma cells." Blood 87, no. 7 (April 1, 1996): 2983–92. http://dx.doi.org/10.1182/blood.v87.7.2983.bloodjournal8772983.
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Iron-regulatory proteins (IRP1 and IRP2) are RNA-binding proteins that bind to stem-loop structures known as iron-responsive elements (IREs). IREs are located in the 5′- or 3′-untranslated regions (UTRs) of specific mRNAs that encode proteins involved in iron homeostasis. The binding of IRPs to 5′ IREs represses translation of the mRNA, whereas the binding of IRPs to 3′ IREs stabilizes the mRNA. IRP1 and IRP2 binding activities are regulated by intracellular iron levels. In addition, nitric oxide (NO.) increases the affinity of IRP1 for IREs. The role of NO. in the regulation of IRP1 and IRP2 in rat hepatoma cells was investigated by using the NO.-generating compound S-nitroso-N- acetylpenicillamine (SNAP), or by stimulating cells with multiple cytokines and lipopolysaccharide (LPS) to induce NO. production. Mitochondrial and IRP1 aconitase activities were decreased in cells producing NO(.). NO. increased IRE binding activity of IRP1, but had no effect on IRE binding activity of IRP2. The increase in IRE binding activity of IRP1 was coincident with the translational repression of ferritin synthesis. Transferrin receptor (TfR) mRNA levels were increased in cells treated with NO.-generating compounds, but not in cytokine- and LPS-treated cells. Our data indicate that IRP1 and IRP2 are differentially regulated by NO. in rat hepatoma cells, suggesting a role for IRP1 in the regulation of iron homeostasis in vivo during hepatic inflammation.
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Bosshart, Herbert, and Michael Heinzelmann. "Arginine-Rich Cationic Polypeptides Amplify Lipopolysaccharide-Induced Monocyte Activation." Infection and Immunity 70, no. 12 (December 2002): 6904–10. http://dx.doi.org/10.1128/iai.70.12.6904-6910.2002.
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ABSTRACT The human neutrophil-derived cationic protein CAP37, also known as azurocidin or heparin-binding protein, enhances the lipopolysaccharide (LPS)-induced release of tumor necrosis factor alpha (TNF-α) in isolated human monocytes. We measured the release of the proinflammatory cytokine interleukin-8 (IL-8) in human whole blood and found that in addition to CAP37, other arginine-rich cationic polypeptides, such as the small structurally related protamines, enhance LPS-induced monocyte activation. As CAP37 and protamines share high levels of arginine content, we tested different synthetic poly-l-amino acids and found that poly-l-arginine, and to a lesser extent poly-l-lysine, increased IL-8 production in LPS-stimulated human whole blood. Protamine-enhanced LPS responses remained unaffected by the presence of free l-arginine or l-lysine, indicating that basic polypeptides but not basic amino acids act synergistically with LPS. In agreement with observations previously reported for CAP37, the LPS-enhancing effect of poly-l-arginine was completely abolished upon antibody blockade of the human LPS receptor, CD14. Protamines, either immobilized or in solution, bound LPS specifically. Poly-l-arginines, protamines, and CAP37 were equally effective in inhibiting binding of LPS to immobilized l-arginines. Taken together, our results suggest a CD14-dependent mechanism by which arginine-rich cationic proteins modulate LPS-induced monocyte activation and support the prediction that other strongly basic proteins could act as amplifiers of LPS responses.
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Haziot, Alain, Xing Y. Lin, Fan Zhang, and Sanna M. Goyert. "Cutting Edge: The Induction of Acute Phase Proteins by Lipopolysaccharide Uses a Novel Pathway That Is CD14-Independent." Journal of Immunology 160, no. 6 (March 15, 1998): 2570–72. http://dx.doi.org/10.4049/jimmunol.160.6.2570.
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Abstract LPS (endotoxin) and proinflammatory cytokines (IL-6, IL-1, and TNF-α) are potent inducers of acute phase proteins (APP). Since LPS induces high levels of these cytokines after its interaction with CD14, a protein expressed on the surface of monocytes and neutrophils, it has been assumed that CD14 mediates the LPS induction of APP expression. To test this hypothesis, CD14-deficient and control mice were injected with low doses of LPS, and the expression of several APP that are normally up-regulated by LPS was measured. CD14-deficient mice showed no alteration in the induction of APP, including serum amyloid A, LPS-binding protein, fibrinogen, or ceruloplasmin; in contrast, C3H/HeJ mice, which carry a mutation in the Lps gene, do not up-regulate the expression of these proteins. These studies show that the up-regulation of APP by LPS utilizes a non-CD14 receptor and requires a functional Lps gene.
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Tsai, Eunice Y., James V. Falvo, Alla V. Tsytsykova, Amy K. Barczak, Andreas M. Reimold, Laurie H. Glimcher, Matthew J. Fenton, David C. Gordon, Ian F. Dunn, and Anne E. Goldfeld. "A Lipopolysaccharide-Specific Enhancer Complex Involving Ets, Elk-1, Sp1, and CREB Binding Protein and p300 Is Recruited to the Tumor Necrosis Factor Alpha Promoter In Vivo." Molecular and Cellular Biology 20, no. 16 (August 15, 2000): 6084–94. http://dx.doi.org/10.1128/mcb.20.16.6084-6094.2000.
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ABSTRACT The tumor necrosis factor alpha (TNF-α) gene is rapidly activated by lipopolysaccharide (LPS). Here, we show that extracellular signal-regulated kinase (ERK) kinase activity but not calcineurin phosphatase activity is required for LPS-stimulated TNF-α gene expression. In LPS-stimulated macrophages, the ERK substrates Ets and Elk-1 bind to the TNF-α promoter in vivo. Strikingly, Ets and Elk-1 bind to two TNF-α nuclear factor of activated T cells (NFAT)-binding sites, which are required for calcineurin and NFAT-dependent TNF-α gene expression in lymphocytes. The transcription factors ATF-2, c-jun, Egr-1, and Sp1 are also inducibly recruited to the TNF-α promoter in vivo, and the binding sites for each of these activators are required for LPS-stimulated TNF-α gene expression. Furthermore, assembly of the LPS-stimulated TNF-α enhancer complex is dependent upon the coactivator proteins CREB binding protein and p300. The finding that a distinct set of transcription factors associates with a fixed set of binding sites on the TNF-α promoter in response to LPS stimulation lends new insights into the mechanisms by which complex patterns of gene regulation are achieved.
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delaTorre, Andrew, Rebecca A. Schroeder, Cecile Punzalan, and Paul C. Kuo. "Endotoxin-Mediated S-Nitrosylation of p50 Alters NF-κB-Dependent Gene Transcription in ANA-1 Murine Macrophages." Journal of Immunology 162, no. 7 (April 1, 1999): 4101–8. http://dx.doi.org/10.4049/jimmunol.162.7.4101.
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Abstract Nitric oxide (NO) regulates cellular function, in part, by S-nitrosylating active site thiol groups of proteins. Ex vivo S-nitrosylation of NF-κB p50 significantly decreases its capacity for DNA binding. To determine the cellular relevance of this observation, we utilized the ANA-l murine macrophage model of endotoxin (LPS)-mediated NO synthesis. In selected instances, the NO synthase inhibitor, l-arginine methyl ester (L-NAME; 100 μM), or the NO donor, S-nitroso-N-acetylcysteine (SNAC; 100 μM), was added. In contrast to that of LPS cells, nuclear extracts from LPS + L-NAME cells demonstrated increased NF-κB DNA binding on gel shift analysis. Addition of SNAC to LPS + L-NAME cells restored binding to a level equivalent to that of LPS cells. Spectrophotometric analysis of NF-κB p50 immunoprecipitates demonstrated S-NO bonds exclusively in LPS cells; these p50 protein isolates retained the same DNA binding characteristics as that of the nuclear extracts. Transfection assays utilizing NF-κB-dependent promoter-reporter constructs demonstrated increased activity in LPS + L-NAME cells compared with LPS cells; nuclear run-on assays confirmed increased transcription of the corresponding genes. These results suggest that LPS-mediated NO synthesis is associated with S-nitrosylation of NF-κB p50 and inhibition of NF-κB-dependent DNA binding, promoter activity, and gene transcription. We conclude that NO can regulate gene transcription by S-nitrosylation of NF-κB.
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Fan, J., D. Char, G. J. Bagby, M. C. Gelato, and C. H. Lang. "Regulation of insulin-like growth factor-I (IGF-I) and IGF-binding proteins by tumor necrosis factor." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 269, no. 5 (November 1, 1995): R1204—R1212. http://dx.doi.org/10.1152/ajpregu.1995.269.5.r1204.
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The purpose of the present study was to determine 1) whether exogenous administration of tumor necrosis factor-alpha (TNF-alpha) alters insulin-like growth factor-I (IGF-I) and IGF-binding proteins (BPs) and 2) whether the enhanced endogenous production of TNF mediates the lipopolysaccharide (LPS)-induced changes in the IGF system. The overnight infusion of murine TNF-alpha reduced circulating concentrations of both growth hormone (GH) and IGF-I in fasted rats. Furthermore, TNF-alpha decreased IGF-I content in liver, gastrocnemius muscle, and pituitary. In contrast, TNF-alpha increased IGF-I content in kidney and brain. IGFBP-1 was increased in plasma, liver, and muscle in response to TNF-alpha. In a second study, rats were injected with LPS after treatment with a neutralizing anti-TNF antibody (Ab), and blood and tissues were collected 4 h later. In LPS-treated rats, plasma concentrations of GH and IGF-I were reduced. LPS also decreased the IGF-I content in liver and skeletal muscle and increased plasma, liver, and muscle concentrations of IGFBP-1. Pretreatment with anti-TNF Ab attenuated the LPS-induced reduction in IGF-I and the increased IGFBP-1 in plasma and liver and completely prevented the decrease in IGF-I observed in muscle. In contrast, the LPS-induced decrease in plasma GH and the increased IGFBP-1 observed in muscle were unaltered by the anti-TNF Ab.(ABSTRACT TRUNCATED AT 250 WORDS)
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Lloyd, Katie L., and Paul Kubes. "GPI-linked endothelial CD14 contributes to the detection of LPS." American Journal of Physiology-Heart and Circulatory Physiology 291, no. 1 (July 2006): H473—H481. http://dx.doi.org/10.1152/ajpheart.01234.2005.
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The inflammatory endothelial response to LPS is critical to the host's surviving a gram-negative bacterial infection. In this study we investigated whether human endothelial cells express the functional coreceptor for LPS, CD14, and most importantly whether it is glycosylphosphatidylinositol (GPI) linked. We also examined whether plasma proteins could reconstitute an LPS response in CD14-inhibited endothelium. RT-PCR- and CD14-specific MAbs demonstrated CD14 expression on primary human umbilical vein endothelial cells (HUVEC) but not passaged HUVEC. The amino acid sequence of endothelial CD14 was 99% homologous to CD14 on monocytes. Endothelium responded to relatively low levels of LPS in the absence of plasma, and this was entirely dependent on CD14. Removal of GPI-linked proteins with phosphatidylinositol-phospholipase C prevented LPS detection and subsequent protein synthesis (E-selectin expression). Endothelial CD14 was sufficient to initiate functional leukocyte recruitment, an event inhibited by blocking its LPS binding epitope and also by removing CD14 from the endothelial surface. Plasma proteins restored only ∼30% of the LPS response in CD14-inhibited endothelium. In conclusion, our results strongly support an important role for endothelial membrane CD14 in the activation of endothelium for leukocyte recruitment.