This is a neutrophil granule-derived antibacterial and monocyte- and fibroblast-specific chemotactic glycoprotein. Binds heparin. The cytotoxic action is limited to many species of Gram-negative bacteria; this specificity may be explained by a strong affinity of the very basic N-terminal half for the negatively charged lipopolysaccharides that are unique to the Gram-negative bacterial outer envelope. It may play a role in mediating recruitment of monocytes in the second wave of inflammation. Has antibacterial activity against the Gram-nagative bacterium P.aeruginosa, this activity is inhibited by LPS from P.aeruginosa. Acting alone, it does not have antimicrobial activity against the Gram-negative bacteria A.actinomycetemcomitans ATCC 29532, A.actinomycetemcomitans NCTC 9709, A.actinomycetemcomitans FDC-Y4, H.aphrophilus ATCC 13252, E.corrodens ATCC 23834, C.sputigena ATCC 33123, Capnocytophaga sp ATCC 33124, Capnocytophaga sp ATCC 27872 or E.coli ML-35. Has antibacterial activity against C.sputigena ATCC 33123 when acting synergistically with either elastase or cathepsin G.
Azurocidin was purified in the presence of phenylmethylsulfonyl fluoride. Electrophoresis revealed at least seven species which exhibited N-terminal sequences consistent with azurocidin. Azurocidin exhibited no bactericidal activity against Capnocytophaga sputigena or other oral bacteria but synergized the bactericidal activity of enzymatically active elastase. Azurocidin also interacted synergistically with cathepsin G.
Killing of Pseudomonas aeruginosa by a 55-kDa bactericidal protein (BP 55), a 30-kDa protein (BP 30), cathepsin G, elastase, and proteinase 3 has been compared. P. aeruginosa was resistant to killing by elastase and proteinase 3. BP 55 at a 50% lethal dose (LD50) of 0.23 micrograms of protein per 5 x 10(6) bacteria per ml killed P. aeruginosa and was far more active than BP 30 and cathepsin G. The LD50s of BP 30 and cathepsin G were 16.9 and 28.3 micrograms of protein per 5 x 10(6) bacteria per ml, respectively. Preincubation of BP 55 or BP 30 with lipopolysaccharide (LPS) from P. aeruginosa inhibited bactericidal activity. The N-terminal amino acid sequence of BP 55 and BP 30 revealed no relationship between the two proteins. However, a monoclonal antibody (AHN-15) reacted with both proteins by Western immunoblot. The bactericidal activity of cathepsin G toward P. aeruginosa appeared to be dependent on the availability of the active site of the enzyme; bactericidal activity was inhibited by phenylmethylsulfonyl fluoride (PMSF) and by the specific cathepsin G inhibitor, Z-Gly-Leu-Phe-CH2Cl. The enzyme and bactericidal activities of cathepsin G were also inhibited by LPS from P. aeruginosa. LPS from P. aeruginosa was shown to be a competitive inhibitor of the enzyme activity of cathepsin G. Elastase enzyme activity was also inhibited noncompetitively by LPS, but the enzyme was not bactericidal. We have concluded that all three bactericidal proteins (BP 55, BP 30, and cathepsin G) may bind to the LPS of the outer membrane of P. aeruginosa. It appears that the enzyme active site must be available for cathepsin G to kill P. aeruginosa and that the active site may be involved in the binding of cathepsin G to P. aeruginosa.
Interacting selectively and non-covalently with heparin, any member of a group of glycosaminoglycans found mainly as an intracellular component of mast cells and which consist predominantly of alternating alpha-(1->4)-linked D-galactose and N-acetyl-D-glucosamine-6-sulfate residues.
Azurocidin/CAP37/HBP is an antimicrobial and chemotactic protein that is part of the innate defenses of human neutrophils. In addition, azurocidin is an inactive serine protease homolog with binding sites for diverse ligands including heparin and the bovine pancreatic trypsin inhibitor (BPTI). The structure of the protein reveals a highly cationic domain concentrated on one side of the molecule and responsible for its strong polarity. To investigate the role of this highly basic region, we produced three recombinant azurocidin mutant proteins that were altered in either one or both of two clusters of 4 basic residues located symmetrically on each side of a central cleft in the cationic domain. Two of the mutant proteins (Loop 3: R5Q, K6Q, R8Q, and R10Q; Loop 4: R61Q, R62Q, R63Q, and R65Q) exhibited little or no change in heparin and BPTI binding or in antimicrobial function. In contrast, the Loop 3/Loop 4 mutant (R5Q, K6Q, R8Q, R10Q, R61Q, R62Q, R63Q, and R65Q) in which all 8 basic residues were replaced showed greatly decreased ability to bind heparin and to kill Escherichia coli and Candida albicans. Thus, we report that the 8 basic residues that were altered in the Loop 3/Loop 4 mutant contribute to the ability of the wild-type azurocidin molecule to bind heparin and to kill E. coli and C. albicans. Because BPTI binding was comparable in wild-type and Loop 3/Loop 4 mutant protein, we conclude that the same 8 basic residues are not involved in the binding of BPTI to azurocidin, supporting the notion that the binding site for BPTI is distinct from the site involved in heparin binding and antimicrobial activity. Finally, we show that removal of all 4 positively charged amino acids in the 20-44 azurocidin sequence (DMC1: R23Q,H24S,H32S,R34Q), a region previously thought to contain an antimicrobial domain, does not affect the activity of the protein against E. coli, Streptococcus faecalis, and C. albicans.
Catalysis of the hydrolysis of internal, alpha-peptide bonds in a polypeptide chain by a catalytic mechanism that involves a catalytic triad consisting of a serine nucleophile that is activated by a proton relay involving an acidic residue (e.g. aspartate or glutamate) and a basic residue (usually histidine).
J. Leukoc. Biol. 66, 634-643 (1999)[PubMed:10534120]
Azurocidin is a multifunctional endotoxin-binding serine protease homolog synthesized during the promyelocytic stage of neutrophil development. To characterize the biosynthesis and processing of azurocidin, cDNA encoding human preproazurocidin was stably transfected to the rat basophilic leukemia cell line RBL-1 and the murine myeloblast-like cell line 32D cl3; cell lines previously utilized to study the related proteins cathepsin G and proteinase 3. After 30 min of pulse radiolabeling, two forms of newly synthesized proazurocidin (34.5 and 37 kDa), differing in carbohydrate content but with protein cores of identical sizes, were recognized. With time, the 34.5-kDa form disappeared, while the 37-kDa form was further processed proteolytically, as judged by digestion with N-glycosidase F. Conversion of high-mannose oligosaccharides into complex forms was shown by acquisition of complete resistance to endoglycosidase H. Radiosequence analysis demonstrated that the amino-terminal seven amino acid propeptide of proazurocidin was removed in a stepwise manner during processing; initial removal of five amino acids was followed by cleavage of a dipeptide. Presence of the protease inhibitors Gly-Phe-diazomethyl ketone, bestatin, or leupeptin inhibited only the cleavage of the dipeptide, thus indicating the involvement of at least two amino-terminal processing enzymes. Translocation of azurocidin to granules was shown by subcellular fractionation. Similar results, with efficient biosynthesis, processing, and targeting to granules in both cell lines, were obtained with a mutant form of human preproazurocidin lacking the amino-terminal heptapropeptide. In conclusion, this investigation is an important addition to our previous studies on related azurophil granule proteins, and provides novel information concerning the biosynthesis and distinctive amino-terminal processing of human azurocidin.
Human neutrophils have an important role in host defense against microbial infection. At different stages of an infectious process, neutrophils progressively up-regulate receptors and release various effector molecules. These are stored in several distinct types of granules with varying propensity to be secreted. Heparin-binding protein (HBP), also known as CAP37 or azurocidin, is a multifunctional, inactive serine-protease homologue. The present work shows that HBP is released from neutrophils on stimulation with secretagogues that do not trigger the secretion of azurophilic granule content. Therefore, the subcellular localization of HBP was investigated in more detail. Immunofluorescence microscopy revealed that HBP was localized close to the plasma membrane. Further analysis by fractionation of postnuclear supernatants from cavitated neutrophils showed that HBP is stored in azurophilic granules and secretory vesicles but that it is also detected to a minor extent in the plasma membrane. These findings were confirmed by immunoelectron microscopy showing that HBP colocalized with marker proteins of azurophilic granules and secretory vesicles. The presence of HBP in secretory vesicles possibly depends on the stage of cell differentiation, since the promyelocytic cell line HL-60 contains less HBP than mature neutrophils, stored exclusively in the less easily mobilized azurophilic granules. Our findings suggest that HBP can be synthesized or targeted to easily mobilized compartments at a late stage of neutrophil maturation. The ability of neutrophils to secrete HBP from secretory vesicles may be important for proinflammatory functions of this protein, such as the alteration of vascular permeability.
Recent evidence suggests that inflammation and immune function in the central nervous system (CNS) may play a considerable role in the progression of many neurodegenerative diseases. It is known that microglia, the CNS equivalent of peripheral blood monocytes, may be instrumental in causing neurotoxicity. However, the mediator(s) that activates microglia to produce toxic substances that orchestrate cell death has yet to be elucidated. We have identified a novel inflammatory molecule, cationic antimicrobial protein of molecular weight 37 kDa (CAP37), to the brains of patients dying from Alzheimer's disease. CAP37 is known to be a potent activator and regulator of monocyte function in the systemic circulation. We hypothesize that CAP37, a mediator previously shown to recruit and activate monocytes in the systemic circulation, may also play a role in CNS inflammation by modulating microglial function. Here we demonstrate that CAP37 is a chemoattractant for microglia and that CAP37-treated microglia express class II major histocompatibility antigens and produce proinflammatory cytokines and chemokines. We conclude that CAP37 has the ability to activate microglial cells and suggest that it has the potential to serve as a neuroinflammatory molecule.
The orderly movement of a glial cell, non-neuronal cells that provide support and nutrition, maintain homeostasis, form myelin, and participate in signal transmission in the nervous system.
Recent evidence suggests that inflammation and immune function in the central nervous system (CNS) may play a considerable role in the progression of many neurodegenerative diseases. It is known that microglia, the CNS equivalent of peripheral blood monocytes, may be instrumental in causing neurotoxicity. However, the mediator(s) that activates microglia to produce toxic substances that orchestrate cell death has yet to be elucidated. We have identified a novel inflammatory molecule, cationic antimicrobial protein of molecular weight 37 kDa (CAP37), to the brains of patients dying from Alzheimer's disease. CAP37 is known to be a potent activator and regulator of monocyte function in the systemic circulation. We hypothesize that CAP37, a mediator previously shown to recruit and activate monocytes in the systemic circulation, may also play a role in CNS inflammation by modulating microglial function. Here we demonstrate that CAP37 is a chemoattractant for microglia and that CAP37-treated microglia express class II major histocompatibility antigens and produce proinflammatory cytokines and chemokines. We conclude that CAP37 has the ability to activate microglial cells and suggest that it has the potential to serve as a neuroinflammatory molecule.
Any process that initiates the directed movement of a motile cell or organism towards a higher concentration in a concentration gradient of a specific chemical.
Recent evidence suggests that inflammation and immune function in the central nervous system (CNS) may play a considerable role in the progression of many neurodegenerative diseases. It is known that microglia, the CNS equivalent of peripheral blood monocytes, may be instrumental in causing neurotoxicity. However, the mediator(s) that activates microglia to produce toxic substances that orchestrate cell death has yet to be elucidated. We have identified a novel inflammatory molecule, cationic antimicrobial protein of molecular weight 37 kDa (CAP37), to the brains of patients dying from Alzheimer's disease. CAP37 is known to be a potent activator and regulator of monocyte function in the systemic circulation. We hypothesize that CAP37, a mediator previously shown to recruit and activate monocytes in the systemic circulation, may also play a role in CNS inflammation by modulating microglial function. Here we demonstrate that CAP37 is a chemoattractant for microglia and that CAP37-treated microglia express class II major histocompatibility antigens and produce proinflammatory cytokines and chemokines. We conclude that CAP37 has the ability to activate microglial cells and suggest that it has the potential to serve as a neuroinflammatory molecule.
The immediate defensive reaction (by vertebrate tissue) to infection or injury caused by chemical or physical agents. The process is characterized by local vasodilation, extravasation of plasma into intercellular spaces and accumulation of white blood cells and macrophages.
Int. J. Surg. Investig. 2, 457-466 (2001)[PubMed:12678126]
BACKGROUND AND OBJECTIVE: CAP37, also known as heparin-binding protein (HBP), is neutrophil-derived protein with multifunctional properties that include monocyte chemotaxis and the enhancement of LPS-induced tumor necrosis factor (TNF-alpha), IL-1, IL-6, and PGE2production from isolated monocytes, which suggest a generalized effect on LPS-induced monocyte activation. In this study, we tested whether HBP amplifies the release of other LPS-responsive cytokines from isolated human monocytes. METHODS: Freshly isolated monocytes from 5 healthy donors were stimulated for 24 h with saline, LPS (10 ng/ml), HBP (10 microg/ml), or a combination of LPS + HBP. Cytokine levels in the supernate were measured with ELISA. ANOVA and Fisher's posthoc test were used to determine significance (p < 0.05). Differential display was used to assess cellular mRNA levels. RESULTS: HBP alone induced the production of IL-8, macrophage inhibitory protein MIP-1alpha, and TNF-alpha. HBP increased the LPS-induced production of IL-8, MIP-1alpha, TNF-alpha, IL-1beta, but HBP did not increase the significant LPS-induced release of IL-10, monocyte chemoattractant protein MCP-1, and IL- 12. Differential display demonstrated that HBP induced an mRNA pattern that was different from the mRNA pattern induced by saline, LPS, or HBP + LPS, indicating multiple and different gene activation. CONCLUSIONS: We conclude that HBP is not a general amplificator of LPS-induced monocyte activation but rather a molecule that targets the production of a distinct set of mediators including pro-inflammatory cytokines such as TNF-alpha and IL-1beta, but not the anti-inflammatory cytokine IL-10, nor IL-12 and MCP-1. The exact intracellular signaling pathways remain unknown but include mechanisms that alter gene transcription.
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.
Recent evidence suggests that inflammation and immune function in the central nervous system (CNS) may play a considerable role in the progression of many neurodegenerative diseases. It is known that microglia, the CNS equivalent of peripheral blood monocytes, may be instrumental in causing neurotoxicity. However, the mediator(s) that activates microglia to produce toxic substances that orchestrate cell death has yet to be elucidated. We have identified a novel inflammatory molecule, cationic antimicrobial protein of molecular weight 37 kDa (CAP37), to the brains of patients dying from Alzheimer's disease. CAP37 is known to be a potent activator and regulator of monocyte function in the systemic circulation. We hypothesize that CAP37, a mediator previously shown to recruit and activate monocytes in the systemic circulation, may also play a role in CNS inflammation by modulating microglial function. Here we demonstrate that CAP37 is a chemoattractant for microglia and that CAP37-treated microglia express class II major histocompatibility antigens and produce proinflammatory cytokines and chemokines. We conclude that CAP37 has the ability to activate microglial cells and suggest that it has the potential to serve as a neuroinflammatory molecule.
Recent evidence suggests that inflammation and immune function in the central nervous system (CNS) may play a considerable role in the progression of many neurodegenerative diseases. It is known that microglia, the CNS equivalent of peripheral blood monocytes, may be instrumental in causing neurotoxicity. However, the mediator(s) that activates microglia to produce toxic substances that orchestrate cell death has yet to be elucidated. We have identified a novel inflammatory molecule, cationic antimicrobial protein of molecular weight 37 kDa (CAP37), to the brains of patients dying from Alzheimer's disease. CAP37 is known to be a potent activator and regulator of monocyte function in the systemic circulation. We hypothesize that CAP37, a mediator previously shown to recruit and activate monocytes in the systemic circulation, may also play a role in CNS inflammation by modulating microglial function. Here we demonstrate that CAP37 is a chemoattractant for microglia and that CAP37-treated microglia express class II major histocompatibility antigens and produce proinflammatory cytokines and chemokines. We conclude that CAP37 has the ability to activate microglial cells and suggest that it has the potential to serve as a neuroinflammatory molecule.
Neutrophil-borne heparin-binding protein (HBP) is a multifunctional protein involved in the progression of inflammation. HBP is stored in neutrophil granules and released upon stimulation of the cells in proximity to endothelial cells. HBP affects endothelial cells in multiple ways; however, the molecular and cellular mechanisms underlying the interaction of HBP with these cells are unknown. Affinity isolation and enzymatic degradation demonstrated that HBP released from human neutrophils binds to endothelial cell-surface proteoglycans, such as syndecans and glypican. Flow cytometry indicated that a significant fraction of proteoglycan-bound HBP is taken up by the endothelial cells, and we used radiolabeled HBP to determine the internalization rate of surface-bound HBP. Confocal and electron microscopy revealed that internalized HBP is targeted to perinuclear compartments of endothelial cells, where it colocalizes with mitochondria. Western blotting of isolated mitochondria from HBP-treated endothelial cells showed that HBP is present in 2 forms - 28 and 22 kDa. Internalized HBP markedly reduced growth factor deprivation-induced caspase-3 activation and protected endothelial cells from apoptosis, suggesting that uptake and intracellular routing of exogenous HBP to mitochondria contributes to the sustained viability of endothelial cells in the context of locally activated neutrophils.
Cationic antimicrobial protein of molecular weight 37 kDa (CAP37) is a multifunctional inflammatory mediator that was originally isolated from human neutrophils and described to possess bactericidal and monocyte-activating functions. More recently its expression in endothelial and epithelial cells in response to inflammatory mediators and its ability to activate endothelial cells and alter permeability has been demonstrated. We hypothesize that CAP37 facilitates the process of transendothelial migration not only because of its potential to act as a chemoattractant but also through its ability to promote leukocyte adhesion to the endothelium by modulating adhesion molecule expression on the endothelium. Here we describe its ability to mediate neutrophil and monocyte adherence to endothelial monolayers in vitro. Using reverse transcriptase-polymerase chain reaction and flow cytometry, we demonstrate its ability to upregulate the adhesion molecules, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin in human umbilical vein and lung microvessel endothelial cells. The identity and kinetics of upregulation of the specific adhesion molecule was dependent on the endothelial cell type, suggesting that adhesion molecules on endothelial cells from different vascular beds are differentially regulated by CAP37. The cell-specific kinetics of adhesion molecule upregulation by CAP37 may influence selective leukocyte migration in certain inflammatory situations.
Any process that activates or increases the frequency, rate or extent of the chemical reactions and pathways resulting in the formation of fractalkine, a chemokine involved in the control of the key regulatory mechanisms of cell trafficking at sites of inflammation.
Recent evidence suggests that inflammation and immune function in the central nervous system (CNS) may play a considerable role in the progression of many neurodegenerative diseases. It is known that microglia, the CNS equivalent of peripheral blood monocytes, may be instrumental in causing neurotoxicity. However, the mediator(s) that activates microglia to produce toxic substances that orchestrate cell death has yet to be elucidated. We have identified a novel inflammatory molecule, cationic antimicrobial protein of molecular weight 37 kDa (CAP37), to the brains of patients dying from Alzheimer's disease. CAP37 is known to be a potent activator and regulator of monocyte function in the systemic circulation. We hypothesize that CAP37, a mediator previously shown to recruit and activate monocytes in the systemic circulation, may also play a role in CNS inflammation by modulating microglial function. Here we demonstrate that CAP37 is a chemoattractant for microglia and that CAP37-treated microglia express class II major histocompatibility antigens and produce proinflammatory cytokines and chemokines. We conclude that CAP37 has the ability to activate microglial cells and suggest that it has the potential to serve as a neuroinflammatory molecule.
Any process that activates or increases the frequency, rate or extent of the chemical reactions and pathways resulting in the formation of interleukin-1 beta.
Recent evidence suggests that inflammation and immune function in the central nervous system (CNS) may play a considerable role in the progression of many neurodegenerative diseases. It is known that microglia, the CNS equivalent of peripheral blood monocytes, may be instrumental in causing neurotoxicity. However, the mediator(s) that activates microglia to produce toxic substances that orchestrate cell death has yet to be elucidated. We have identified a novel inflammatory molecule, cationic antimicrobial protein of molecular weight 37 kDa (CAP37), to the brains of patients dying from Alzheimer's disease. CAP37 is known to be a potent activator and regulator of monocyte function in the systemic circulation. We hypothesize that CAP37, a mediator previously shown to recruit and activate monocytes in the systemic circulation, may also play a role in CNS inflammation by modulating microglial function. Here we demonstrate that CAP37 is a chemoattractant for microglia and that CAP37-treated microglia express class II major histocompatibility antigens and produce proinflammatory cytokines and chemokines. We conclude that CAP37 has the ability to activate microglial cells and suggest that it has the potential to serve as a neuroinflammatory molecule.
Any process that activates or increases the frequency, rate or extent of the chemical reactions and pathways resulting in the formation of MHC class II.
Evidence
1:
Inferred from Expression PatternUniProtKB
Recent evidence suggests that inflammation and immune function in the central nervous system (CNS) may play a considerable role in the progression of many neurodegenerative diseases. It is known that microglia, the CNS equivalent of peripheral blood monocytes, may be instrumental in causing neurotoxicity. However, the mediator(s) that activates microglia to produce toxic substances that orchestrate cell death has yet to be elucidated. We have identified a novel inflammatory molecule, cationic antimicrobial protein of molecular weight 37 kDa (CAP37), to the brains of patients dying from Alzheimer's disease. CAP37 is known to be a potent activator and regulator of monocyte function in the systemic circulation. We hypothesize that CAP37, a mediator previously shown to recruit and activate monocytes in the systemic circulation, may also play a role in CNS inflammation by modulating microglial function. Here we demonstrate that CAP37 is a chemoattractant for microglia and that CAP37-treated microglia express class II major histocompatibility antigens and produce proinflammatory cytokines and chemokines. We conclude that CAP37 has the ability to activate microglial cells and suggest that it has the potential to serve as a neuroinflammatory molecule.
Recent evidence suggests that inflammation and immune function in the central nervous system (CNS) may play a considerable role in the progression of many neurodegenerative diseases. It is known that microglia, the CNS equivalent of peripheral blood monocytes, may be instrumental in causing neurotoxicity. However, the mediator(s) that activates microglia to produce toxic substances that orchestrate cell death has yet to be elucidated. We have identified a novel inflammatory molecule, cationic antimicrobial protein of molecular weight 37 kDa (CAP37), to the brains of patients dying from Alzheimer's disease. CAP37 is known to be a potent activator and regulator of monocyte function in the systemic circulation. We hypothesize that CAP37, a mediator previously shown to recruit and activate monocytes in the systemic circulation, may also play a role in CNS inflammation by modulating microglial function. Here we demonstrate that CAP37 is a chemoattractant for microglia and that CAP37-treated microglia express class II major histocompatibility antigens and produce proinflammatory cytokines and chemokines. We conclude that CAP37 has the ability to activate microglial cells and suggest that it has the potential to serve as a neuroinflammatory molecule.
Any process that activates or increases the frequency, rate or extent of the chemical reactions and pathways resulting in the formation of tumor necrosis factor, an inflammatory cytokine produced by macrophages/monocytes during acute inflammation and which is responsible for a diverse range of signaling events within cells, leading to necrosis or apoptosis.
Recent evidence suggests that inflammation and immune function in the central nervous system (CNS) may play a considerable role in the progression of many neurodegenerative diseases. It is known that microglia, the CNS equivalent of peripheral blood monocytes, may be instrumental in causing neurotoxicity. However, the mediator(s) that activates microglia to produce toxic substances that orchestrate cell death has yet to be elucidated. We have identified a novel inflammatory molecule, cationic antimicrobial protein of molecular weight 37 kDa (CAP37), to the brains of patients dying from Alzheimer's disease. CAP37 is known to be a potent activator and regulator of monocyte function in the systemic circulation. We hypothesize that CAP37, a mediator previously shown to recruit and activate monocytes in the systemic circulation, may also play a role in CNS inflammation by modulating microglial function. Here we demonstrate that CAP37 is a chemoattractant for microglia and that CAP37-treated microglia express class II major histocompatibility antigens and produce proinflammatory cytokines and chemokines. We conclude that CAP37 has the ability to activate microglial cells and suggest that it has the potential to serve as a neuroinflammatory molecule.
Protein kinase C-activating G-protein coupled receptor signaling pathwaydefinition[GO:0007205]
The series of molecular signals generated as a consequence of a G-protein coupled receptor binding to its physiological ligand, where the pathway proceeds with activation of protein kinase C (PKC). PKC is activated by second messengers including diacylglycerol (DAG).
Recent evidence suggests that inflammation and immune function in the central nervous system (CNS) may play a considerable role in the progression of many neurodegenerative diseases. It is known that microglia, the CNS equivalent of peripheral blood monocytes, may be instrumental in causing neurotoxicity. However, the mediator(s) that activates microglia to produce toxic substances that orchestrate cell death has yet to be elucidated. We have identified a novel inflammatory molecule, cationic antimicrobial protein of molecular weight 37 kDa (CAP37), to the brains of patients dying from Alzheimer's disease. CAP37 is known to be a potent activator and regulator of monocyte function in the systemic circulation. We hypothesize that CAP37, a mediator previously shown to recruit and activate monocytes in the systemic circulation, may also play a role in CNS inflammation by modulating microglial function. Here we demonstrate that CAP37 is a chemoattractant for microglia and that CAP37-treated microglia express class II major histocompatibility antigens and produce proinflammatory cytokines and chemokines. We conclude that CAP37 has the ability to activate microglial cells and suggest that it has the potential to serve as a neuroinflammatory molecule.
Human neutrophils have an important role in host defense against microbial infection. At different stages of an infectious process, neutrophils progressively up-regulate receptors and release various effector molecules. These are stored in several distinct types of granules with varying propensity to be secreted. Heparin-binding protein (HBP), also known as CAP37 or azurocidin, is a multifunctional, inactive serine-protease homologue. The present work shows that HBP is released from neutrophils on stimulation with secretagogues that do not trigger the secretion of azurophilic granule content. Therefore, the subcellular localization of HBP was investigated in more detail. Immunofluorescence microscopy revealed that HBP was localized close to the plasma membrane. Further analysis by fractionation of postnuclear supernatants from cavitated neutrophils showed that HBP is stored in azurophilic granules and secretory vesicles but that it is also detected to a minor extent in the plasma membrane. These findings were confirmed by immunoelectron microscopy showing that HBP colocalized with marker proteins of azurophilic granules and secretory vesicles. The presence of HBP in secretory vesicles possibly depends on the stage of cell differentiation, since the promyelocytic cell line HL-60 contains less HBP than mature neutrophils, stored exclusively in the less easily mobilized azurophilic granules. Our findings suggest that HBP can be synthesized or targeted to easily mobilized compartments at a late stage of neutrophil maturation. The ability of neutrophils to secrete HBP from secretory vesicles may be important for proinflammatory functions of this protein, such as the alteration of vascular permeability.
Protein involved in the movement of a cell, or organism, along a concentration gradient of a chemotactic agent, such as a protein which causes, mediates or responds to chemotaxis. Chemotactic molecules such as sugars, peptides, cell metabolites, cell-wall or membrane lipids bind to cell surface receptors and trigger activation of intracellular signaling pathways, as well as remodeling of the cytoskeleton through the activation or inhibition of various actin-binding proteins.
Protein which has deleterious effects on any type of microbe. Microbe is a general term for microscopic unicellular organisms, such as bacteria, archaea, fungi and protista. While the term microbe is often also used for viruses, we do not apply the keyword antimicrobial to antiviral proteins.
A reference proteome is a set of protein sequences derived from a complete proteome which constitutes a defined standard for a particular user community. Reference proteomes are manually defined according to a number of criteria. They cover the proteomes of well- studied model organisms and other proteomes of interest for biomedical and biotechnological research. Reference proteomes have been selected to provide broad coverage of the tree of life, and constitute a representative cross-section of the taxonomic diversity to be found within UniProtKB.
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