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)

CAP37 (cationic antimicrobial protein of molecular mass 37 kDa) is a multifunctional protein isolated from the granules of human neutrophils. It is antibiotic and chemotactic and binds lipopolysaccharide. A synthetic peptide, amino acid sequence NQGRHFCGGALIHARFVMTAASCFQ, based on residues 20-44 of CAP37 protein mimics its antibiotic and lipopolysaccharide binding action. Peptide 20-44, at the concentrations tested, has antibacterial activity against Salmonella typhimurium, Pseudomonas aeruginosa, Escherichia coli, Enterococcus faecalis, and Staphylococcus aureus. The bactericidal action of the peptide was pH dependent, with maximum activity at pH 5.0 and pH 5.5 and decreased activity at pH 7.0. Various truncations, substitutions, and other modifications in the sequence deteriorate its activity. Free sulfhydryl groups and/or disulfide bridge formation are required for optimum antibiotic activity, since substitution of serines for, or alkylation of, cysteine residues 26 and 42 eliminates bactericidal activity. Evidently amino acids 20-44 represent an important, perhaps principal, antibacterial domain of CAP37. This peptide should provide new insight into the mechanism of antimicrobial activity of CAP37 and may serve as a model for new, useful, synthetic antibiotics.
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PMID:Synthetic bactericidal peptide based on CAP37: a 37-kDa human neutrophil granule-associated cationic antimicrobial protein chemotactic for monocytes. 850 27

The lipid A component of lipopolysaccharide (LPS) derived from Escherichia coli has been implicated as a significant mediator in the development of circulatory and metabolic dysfunction and lethality associated with sepsis. A synthetic peptide corresponding to amino acid residues 20 through 44 of the neutrophil-derived 37-kDa cationic antimicrobial protein (CAP37 P(20-44)) possesses lipid A binding characteristics which may be useful in attenuating in vivo responses induced during circumstances of endotoxemia, including sepsis. The E. coli LPS to be used in the in vivo study was shown to be attenuated by CAP37 P(20-44) in a dose-dependent manner in the in vitro reaction with Limulus amoebocyte lysate. Intravenous infusion of CAP37 P(20-44) (1.5 or 3.0 mg/kg of body weight) with E. coli LPS (250 microg/kg over 30 min) into conscious, unrestrained rats prevented LPS-induced hyperdynamic and hypodynamic circulatory shock, hyperlactacidemia, and leukopenia in a dose-related fashion. CAP37 P(20-44) (0.2, 1.0, and 5.0 mg/kg) administered intravenously to conscious, actinomycin D-sensitized rats following a lethal dose of LPS neutralized LPS toxicity, resulting in dose-dependent 7-day survival rates of 30, 50, and 80%, respectively. CAP37 P(20-44) (5.0 mg/kg) significantly inhibited the endotoxin-induced increase in circulating tumor necrosis factor alpha in sensitized rats. These data demonstrate that CAP37 P(20-44) has the capacity to abolish in vivo biological responses to LPS that are relevant to human sepsis and to significantly neutralize the toxicity of circulating E. coli LPS.
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PMID:A synthetic lipopolysaccharide-binding peptide based on the neutrophil-derived protein CAP37 prevents endotoxin-induced responses in conscious rats. 919 53

Activated polymorphonuclear leukocytes release heparin-binding protein (HBP; also known as CAP37 or azurocidin) from azurophilic granules. HBP is a strong chemoattractant for monocytes that also prolongs monocyte survival and potentiates endotoxin (lipopolysaccharide [LPS])-induced production of tumor necrosis factor alpha (TNF-alpha). We investigated the binding of fluorescein isothiocyanate-conjugated HBP to human monocytes in the presence of EDTA and the polysaccharide fucoidan. EDTA, which chelates divalent cations, has been widely used to study the role of divalent cations in receptor-ligand interactions or enzyme activity. Fucoidan has been used to inhibit the binding of various ligands to scavenger receptors or selectins. Scavenger receptors are multiligand receptors that mediate endocytosis of proteases, protease-inhibitor complexes, lipoproteins, and LPS-lipid A. Fucoidan also interferes with leukocyte rolling by binding to L-selectins (expressed on leukocytes) and P-selectins (expressed on platelets and endothelium). We demonstrate that the binding of the neutrophil-derived protein HBP to monocytes is inhibited in the presence of EDTA and fucoidan. In addition, fucoidan and EDTA abrogate the enhancing effect of HBP on LPS-induced TNF-alpha production. These data provide supporting evidence that HBP binds to a receptor expressed on monocytes. This receptor is dependent on divalent cations and is possibly related to the scavenger receptor. Furthermore, we demonstrate that fucoidan, by itself, stimulates TNF-alpha release from isolated monocytes in a CD14-independent fashion. This is an important finding for the interpretation of results from studies that use fucoidan to "block" either scavenger receptors or L- or P-selectins.
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PMID:Modulation of lipopolysaccharide-induced monocyte activation by heparin-binding protein and fucoidan. 982 63

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-alpha) 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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PMID:Arginine-rich cationic polypeptides amplify lipopolysaccharide-induced monocyte activation. 1243 68

Human cationic antimicrobial protein, CAP37, is released from neutrophil granules during infection. CAP37 attracts monocytes, binds Gram-negative endotoxin (lipopolysaccharide, LPS), is bactericidal for a range of Gram-negative bacteria, and reduces mortality in murine polymicrobial sepsis. Here, we report that recombinant CAP37 specifically targets murine peritoneal macrophages. Under steady-state conditions, the bulk of cell-associated CAP37 was localized at the plasma membrane. However, a fraction of CAP37 gained access to the endocytic system, but did not accumulate in recycling endosomes or in the trans-Golgi network (TGN). Instead, CAP37 was internalized by fluid phase endocytosis and accumulated in a prelysosomal compartment. Macrophages that were preexposed to CAP37 exhibited diminished LPS responsiveness, as determined by analysis of c-Jun phosphorylation. Further examination showed that pretreatment with CAP37 reduced the ability of macrophages to bind LPS. Taken together, these observations demonstrate that prolonged exposure to CAP37 desensitizes macrophages to LPS and suggest that this protein plays a novel anti-inflammatory role in polymicrobial sepsis.
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PMID:Human neutrophil-derived CAP37 inhibits lipopolysaccharide-induced activation in murine peritoneal macrophages. 1527 64