Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.37 (neutrophil elastase)
 4,078 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human heparin-binding protein (hHBP) is a recently discovered proteolytically inactive neutrophil elastase homologue with sequence identity to azurocidin and CAP37. The protein has antibacterial properties and chemotactic activity toward monocytes. In the present work, we show that monocytes, cultured under serum-free conditions, developed morphological changes and formed multicellular aggregates 4 h after the addition of hHBP at a concentration of 10 micrograms/ml. However, after prolonged incubation (11 days) with unchanged medium, the cells spread again. The hHBP-treated cells had a two- to threefold increase in survival compared to control cells, measured using trypan blue as an indicator of living cells. Differentiation of the alive cells to macrophages was detected by changes in morphology, a threefold increase in protein content, and a three- to fourfold increase in acid phosphatase activity. When monocytes in parallel experiments were labelled with [35S]methionine de novo synthesis and secretion of thrombospondin in a dose-dependent manner was observed after 16 h, with half-maximal secretion at 2 micrograms hHBP/ml and a maximal 12-fold increase in secretion with respect to controls at 16 micrograms/ml. Supplementary labeling with [35S]sulfate revealed that the same monocytes down-regulated the secretion of a large proteoglycan (300-400 kd), apparently also with a half-maximal decrease rate at 2 micrograms/ml hHBP. Exposure of confluent fibroblast and endothelial cell monolayers to hHBP (10 micrograms/ml) in the absence of fetal calf serum resulted in cell contraction leaving gaps between cells, the phenomenon being recognizable within 4 h after addition of hHBP. Addition of fetal calf serum to a concentration of 10% completely restored the monolayers. A unique role of hHBP in host defense involving recruitment of monocytes and a key function of hHBP in neutrophil extravasation in response to inflammatory chemotactic signals such as leukotriene B4, complement peptide C5a, and N-formyl-methionyl-leucyl-phenylalanine are suggested.
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PMID:A neutrophil-derived proteolytic inactive elastase homologue (hHBP) mediates reversible contraction of fibroblasts and endothelial cell monolayers and stimulates monocyte survival and thrombospondin secretion. 156 96

Cationic antimicrobial protein CAP37 (Mr = 37 kD) is derived from the azurophilic granules of human PMN. In vitro and in vivo studies demonstrate that CAP37 is a novel monocyte-specific chemoattractant. The N-terminal amino acid sequence of CAP37 shares significant homology with a number of inflammatory molecules with protease activity including elastase and cathepsin G. However, substitutions in the catalytic triad (serine for a histidine at position 41 and glycine for a serine at position 175), may account for its lack of serine protease activity. A full length cDNA for CAP37 was identified in an HL60 cDNA library screened with oligonucleotide probes designed from the N-terminal amino acid sequence. Sequencing of the cDNA reveals a protein of 225 amino acids with significant nucleotide homology to cathepsin G and human neutrophil elastase.
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PMID:Human neutrophil granule cationic protein CAP37 is a specific macrophage chemotaxin that shares homology with inflammatory proteinases. 175 83

Human cationic antimicrobial protein (CAP37) is a neutrophil granule protein with monocyte chemotactic and antibacterial activity. A CAP37 cDNA clone of 899 bp was isolated from an HL-60 cDNA library using degenerate oligonucleotide probes based on partial N-terminal sequence of the CAP37 protein. The cDNA sequence predicts an open reading frame of 753 bp encoding a protein of 251 amino acids. A 26-residue eukaryotic signal peptide and a potential 7 amino acid pro-peptide are present at the N-terminus of the protein. The cDNA sequence also predicts three N-linked glycosylation attachment sites and eight intramolecular cysteines. The deduced amino acid sequence of CAP37 shows 44, 42, and 32% homology at the amino acid level to neutrophil elastase, myeloblastin, and cathepsin G, respectively, suggesting that CAP37 is a member of the serine protease gene family. CAP37 does not possess serine protease activity probably due to mutations in two of three residues in the catalytic triad of the "charge relay system." Whereas CAP37 is expressed in undifferentiated HL-60 cells no message is detected in mature neutrophils.
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PMID:Cloning of the cDNA for the serine protease homolog CAP37/azurocidin, a microbicidal and chemotactic protein from human granulocytes. 191 11

We report the amino acid sequence of CAP37, a human neutrophil granule protein with antibacterial and monocyte-specific chemotactic activity. CAP37 is a single-chain protein consisting of 222 amino acid residues. It has three N-glycosylation sites, at Asn residues 100, 114 and 145. Some species of CAP37 are glycosylated at all three sites; some at Asn-114 alone, others at Asn-114 and Asn-110 or Asn-145. CAP37 has 45% sequence identity to human neutrophil elastase, and 30-37% identity to several other granule serine proteinases. Despite these similarities, CAP37 is not a serine proteinase because the active site residues serine and histidine are replaced.
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PMID:Amino acid sequence of CAP37, a human neutrophil granule-derived antibacterial and monocyte-specific chemotactic glycoprotein structurally similar to neutrophil elastase. 222 32

Cosmid clones containing the genes for the human and murine natural killer cell serine protease Met-ase (gene symbol GZMM; granzyme M) were identified by screening human and murine cosmid libraries with rat Met-ase (RNK-Met-1) cDNA. The human gene has a size of 7.5 kb and an exon-intron structure identical to that of serine protease genes located on human chromosomes 5q11-q12, 14q11.2, and 19p13.3 that are expressed by lymphocytes, mast cells, or myelomonocyte precursors. Using cosmid DNA as a probe for fluorescence in situ hybridization, we identified the chromosomal position of human Met-ase as 19p13.3. Interphase studies with two differentially labeled probes for Met-ase and the azurocidin (AZU1), proteinase 3 (PRTN3), and neutrophil elastase (ELA2) gene cluster revealed that the distance of Met-ase from this gene cluster is in the range of 200 to 500 kb. Using differentially labeled mouse cosmid probes, we also mapped the murine gene for Met-ase to chromosomal band 10C, close to the gene for lamin B2. Thus, the Met-ase, AZU1, PRTN3, and ELA2 genes fall into an established region of homology between mouse chromosomal band 10C and human 19p13.3.
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PMID:The human Met-ase gene (GZMM): structure, sequence, and close physical linkage to the serine protease gene cluster on 19p13.3. 771 95

Neutrophil elastase, proteinase-3, and azurocidin are primary components of neutrophil azurophilic granules and are encoded by closely linked genes (gene symbols ELA2, PRTN3, and AZU1, respectively) in a region of approximately 50 kb. These genes are coordinately expressed in a granulocyte-specific fashion, but the mechanisms defining this pattern of expression are unknown. To understand the role of chromatin organization in governing the expression of ELA2, PRTN3, and AZU1, we mapped this region of chromosome 19 and identified the adipsin (complement factor D) gene in proximity to the 3' end of ELA2. We then examined the changes in chromatin structure at the locus which accompany myeloid cell differentiation and identified 17 DNase I hypersensitive sites (DHS 1 to 17) in U-937 cells, an early myelomonocytic cell line expressing high levels of neutrophil elastase. Chemically induced differentiation and concomitant downregulation of AZU1, PRTN3, and ELA2 transcription in U-937 cells is not accompanied by changes in the DHS-pattern. Mature neutrophils, however, do not carry any of these hypersensitive sites, indicating a large degree of chromatin remodeling at this locus accompanying terminal granulocytic differentiation. Sixteen of the 17 DHS identified in U-937 cells are also present in the HL-60 myelomonocytic cell line. Hematopoietic cell lines representing the early erythroid and lymphocyte lineages, and a nonhematopoietic cell line display a subset of the hypersensitive sites. The altered chromatin structure specific to cells that actively transcribe the AZU1-PRTN3-ELA2 genes suggests that chromatin reorganization is an important mechanism regulating the myeloid-specific transcription of this gene cluster.
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PMID:Changes in chromatin organization at the neutrophil elastase locus associated with myeloid cell differentiation. 1057 86

Extensive copy number polymorphism was recently reported for innate immunity-related alpha-defensin genes DEFA1 and DEFA3 and beta-defensin genes DEFB4, DEFB103, and DEFB104. To establish whether such polymorphisms are a common feature of innate immune genes we used quantitative real-time PCR to determine the copy numbers of seven genes whose products have important innate immune functions. The genes encoding lysozyme, lactoferrin, cathelicidin antimicrobial peptide (hCAP18/LL-37), cathepsin G, bactericidal/permeability-increasing protein, azurocidin (CAP37/heparin-binding protein), and neutrophil elastase were each found to be single copy per haploid genome. These findings, along with the recent observation that defensin genes DEFA4, DEFA5, DEFA6, and DEFB1 are single copy, suggest that copy number polymorphisms are not a common feature of the innate immune genome but are restricted to a small subset of innate immunity-related genes.
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PMID:Copy number polymorphisms are not a common feature of innate immune genes. 1661 5

Neutrophils are the innate immune system's first line of defense. Neutrophils play a critical role in protecting the host against infectious pathogens, resolving sterile injuries, and mediating inflammatory responses. The granules of neutrophils and their constituent proteins are central to these functions. Although neutrophils may exert a protective role upon acute inflammatory conditions or insults, continued activity of neutrophils in chronic inflammatory diseases can contribute to tissue damage. Neutrophil granule proteins are involved in a number of chronic inflammatory conditions and diseases. However, the functions of these proteins in neuroinflammation and chronic neuroinflammatory diseases, including Alzheimer's disease (AD), remain to be elucidated. In this review, we discuss recent findings from our lab and others that suggest possible functions for neutrophils and the neutrophil granule proteins, CAP37, neutrophil elastase, and cathepsin G, in neuroinflammation, with an emphasis on AD. These findings reveal that neutrophil granule proteins may exert both neuroprotective and neurotoxic effects. Further research should determine whether neutrophil granule proteins are valid targets for therapeutic interventions in chronic neuroinflammatory diseases.
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PMID:The role of neutrophil granule proteins in neuroinflammation and Alzheimer's disease. 3014 99