Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.2.1.17 (lysozyme)
 21,489 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Menadione is a synthetic derivative of the natural vitamins K with antiinflammatory activity among its potentially significant clinical properties. We have found this agent to stimulate the production of superoxide anion (O2-) in human polymorphonuclear leukocytes (PMN) and dimethylsulfoxide-differentiated HL-60 cells in a time-, cell number-, and drug concentration-dependent manner. Conversely, menadione attenuates both O2- production and lysozyme release in cells stimulated by phorbol myristate acetate (PMA), fMet-Leu-Phe, or Ca2+ ionophore. 4-Acetamido-4'-isothiocyano-2-2'-disulfonic acid stilbene and 4,4'-diisothiocyano-2-2'disulfonic acid stilbene, agents which inhibit transmembrane O2-) flux, do not alter menadione's effects on superoxide dismutase (SOD) inhibitable cytochrome c reduction in resting or PMA-stimulated PMN. Likewise, quinone reductase inhibitors, warfarin and dicumarol, known to attenuate vitamin K-dependent responses and enhance quinone-mediated oxidative stress, have no effect upon menadione-stimulated O2- production. Furthermore, menadione-induced suppression of stimulus-mediated lysozyme release is not reversed by cotreatment with oxygen metabolite scavenging enzymes SOD and catalase. Nevertheless, under conditions of restricted oxygen supply, the suppressive effect of menadione on stimulant-induced lysozyme release is greatly diminished. Thus, although pharmacological manipulation suggests otherwise, there appears to exist at least a component of the inhibitory activity of menadione that is oxygen dependent, and may be oxidative stress-related.
 ...
PMID:Alteration of human granulocyte functional responses by menadione. 170 Jun 67

Upon exposure to the bacterial chemotactic peptide fMet-Leu-Phe, human neutrophils release lysozyme and generate superoxide anions (O2.-). The synthetic lipoamino acid N-palmitoyl-S-[2,3-bis(palmitoyloxy)-(2RS)-propyl]-(R)-cysteine (Pam3Cys), which is derived from the N-terminus of bacterial lipoprotein, when attached to Ser-(Lys)4 [giving Pam3Cys-Ser-(Lys)4], activated O2.- formation and lysozyme release in human neutrophils with an effectiveness amounting to about 15% of that of fMet-Leu-Phe. Palmitic acid, muramyl dipeptide, lipopolysaccharide and the lipopeptides Pam3Cys-Ala-Gly, Pam3Cys-Ser-Gly, Pam3Cys-Ser, Pam3Cys-OMe and Pam3Cys-OH did not activate O2.- formation. Pertussis toxin, which ADP-ribosylates guanine-nucleotide-binding proteins (G-proteins) and functionally uncouples formyl peptide receptors from G-proteins, prevented activation of O2.- formation by fMet-Leu-Phe and inhibited Pam3Cys-Ser-(Lys)4-induced O2.- formation by 85%. Lipopeptide-induced exocytosis was pertussis-toxin-insensitive. O2.- formation induced by Pam3Cys-Ser-(Lys)4 and fMet-Leu-Phe was enhanced by cytochalasin B, by a phorbol ester and by a diacylglycerol kinase inhibitor. Addition of activators of adenylate cyclase and removal of extracellular Ca2+ inhibited O2.- formation by fMet-Leu-Phe and Pam3Cys-Ser-(Lys)4 to different extents. Pam3Cys-Ser-(Lys)4 synergistically enhanced fMet-Leu-Phe-induced O2.- formation and primed neutrophils to respond to the chemotactic peptide at non-stimulatory concentrations. Our data suggest the following. (1) Pam3Cys-Ser-(Lys)4 activates neutrophils through G-proteins, involving pertussis-toxin-sensitive and -insensitive processes. (2) The signal transduction pathways activated by fMet-Leu-Phe and Pam3Cys-Ser-(Lys)4 are similar but not identical. (3) In inflammatory processes, bacterial lipoproteins and chemotactic peptides may interact synergistically to activate O2.- formation, leading to enhanced bactericidal activity.
 ...
PMID:Activation of superoxide formation and lysozyme release in human neutrophils by the synthetic lipopeptide Pam3Cys-Ser-(Lys)4. Involvement of guanine-nucleotide-binding proteins and synergism with chemotactic peptides. 216 Feb 37

The role of tyrosine kinases in the responses of human neutrophils to chemotactic factors was examined using the recently described inhibitor erbstatin. Pre-incubation with erbstatin decreased the amount of tyrosine phosphorylation induced by the formylated oligopeptide formyl-methionyl-leucyl-phenylalanine (fMet-Leu-Phe) without effecting the binding of [3H]-fMet-Leu-Phe. Erbstatin also dose-dependently inhibited the production of superoxide anion induced by fMet-Leu-Phe and platelet-activating factor, but did not affect the oxidative burst induced by either the calcium ionophore A23187 or the phorbol ester phorbol 12-myristate 13-acetate. Furthermore, erbstatin diminished the cytosolic acidification elicited by fMet-Leu-Phe, platelet-activating factor, and leukotriene B4. In contrast, erbstatin was without effect on the increase in the levels of cytoplasmic free calcium and polymerized actin elicited by fMet-Leu-Phe, C5a, leukotriene B4 and platelet-activating factor, whereas the increase in cytoplasmic free calcium elicited by platelet-derived growth factor was inhibited by erbstatin. In addition, erbstatin affected neither the release of elastase stimulated by these agonists nor the release of beta-glucosaminidase, lysozyme or vitamin B12-binding protein induced by fMet-Leu-Phe. These results indicate that tyrosine protein kinases are involved in the signaling pathways employed by chemotactic factors in the stimulation of selective functional responses (and superoxide production in particular) in human neutrophils.
 ...
PMID:Selective inhibition of human neutrophil functional responsiveness by erbstatin, an inhibitor of tyrosine protein kinase. 217 35

The addition of low concentrations of the chemotactic factor fMet-Leu-Phe to rabbit neutrophils in the absence of cytochalasin B produces very little superoxide. This level of superoxide can be greatly increased in neutrophils pretreated for 30 min with 10 microM of the diacyl-glycerol kinase inhibitor R59022. This potentiation occurs also in the presence of cytochalasin B. In addition, while the small level of superoxide generated by fMet-Leu-Phe is not inhibited by the protein kinase C inhibitor 1-(5-isoquinoline-sulfonyl)-2-methyl piperazine (H-7), the increase by R59022 is completely abolished by this compound. In addition, this increase can be potentiated further by leupeptin. Unlike superoxide generation, the release of lysozyme or N-acetyl-beta-glucosaminidase produced by fMet-Leu-Phe is not stimulated by R59022. The results presented here suggest that stimulation of the oxidative burst requires the generation and the maintenance of a sufficient amount of diacylglycerol and/or the rearrangement of the cytoskeleton such as the inhibition of actin polymerization. Furthermore, the membrane-associated form of protein kinase C is the one responsible for the activation of the oxidative burst. The relationship between protein kinase C activation and the stimulated oxidative burst and the physiological role of chemotactic factors in the functions of the neutrophils are discussed.
 ...
PMID:The diacylglycerol kinase inhibitor R59022 potentiates superoxide production but not secretion induced by fMet-Leu-Phe: effects of leupeptin and the protein kinase C inhibitor H-7. 282 10

The aim for the present studies is to examine the relationship between the phosphorylation of the 47-kDa protein and some neutrophil responses such as degranulation, the synergistic effect of PMA on calcium ionophore-induced degranulation, superoxide generation, and the priming of the oxidative burst produced by the chemotactic factor fMet-Leu-Phe and phorbol 12-myristate 13-acetate (PMA). Incubation of neutrophils with the protein kinase inhibitor 1-(5-isoquinoline-sulfonyl)-2-methylpiperazine (H-7) inhibits the phosphorylation of the 47-kDa protein produced by PMA and fMet-Leu-Phe but does not affect lysozyme release induced by the same stimuli or fMet-Leu-Phe-induced N-acetyl-beta-glucosaminidase release. Furthermore, the synergistic effect of PMA on the A23187-induced degranulation is not inhibited by H-7. Also, pretreatment of the cells with H-7 inhibits superoxide production produced by PMA but not by fMet-Leu-Phe. The inhibitory effect of H-7 is more pronounced on the rate than on the extent of PMA-induced superoxide release. On the other hand, N-(2-guanidinoethyl)-5-isoquinolinesulfonamide hydrochloride, HA-1004, a less potent protein kinase inhibitor, has no inhibitory effect on superoxide generation produced by fMet-Leu-Phe or PMA. In the case of superoxide production, the addition of low concentrations of PMA to rabbit neutrophils primes these cells to the subsequent stimulation by fMet-Leu-Phe, dramatically increasing the effect. Conversely, low concentrations of fMet-Leu-Phe prime the cells to PMA stimulation. The stimulation by PMA of cells primed with fMet-Leu-Phe is inhibited by H-7. Moreover, the priming effect by PMA is also inhibited by H-7. This inhibition is less pronounced at a low concentration of PMA. On the other hand, in the case of human neutrophils, the priming effect of PMA is not inhibited by H-7. These results suggest several points. First, phosphorylation of the protein identified on two-dimensional gel electrophoresis as having a molecular weight of 47 kDa and PI of 4.9 is not necessary for degranulation produced by either PMA or fMet-Leu-Phe. Second, the phosphorylation of the 47-kDa protein is not necessary for superoxide generation, at least in the case of fMet-Leu-Phe and possibly for other stimuli. Third, in rabbit neutrophils, both the priming and stimulation of superoxide production with PMA are inhibited by H-7. In human neutrophils, the priming by PMA is not affected by H-7.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Dissociation of the 47-kilodalton protein phosphorylation from degranulation and superoxide production in neutrophils. 282 26

Human neutrophils treated with pertussis toxin had decreased functional responses to several agents including zymosan-treated serum, heat-aggregated immunoglobulin, platelet-activating factor, and fMet-Leu-Phe. Responses affected include superoxide generation and release of lysozyme. The degree and type of inhibition was dependent on the individual receptor and the cellular response studied. Measurement of intracellular calcium levels with quin-2 showed that both fMet-Leu-Phe- and platelet-activating factor-mediated increases in quin-2 fluorescence were diminished as a result of pertussis toxin treatment. fMet-Leu-Phe-mediated calcium uptake was also inhibited. However, under conditions where fMet-Leu-Phe-mediated effects on cell function were completely abolished, only a partial inhibition of 3,4,5-trimethoxybenzoic acid 8-(diethylamino)octyl ester (TMB-8) sensitive calcium uptake was observed. A study of the linked reactions of chemotaxis, capping, and shape change revealed that chemotaxis was inhibited regardless of the chemoattractant utilized (zymosan-treated serum, fMet-Leu-Phe, and platelet-activating factor) and the associated reactions of Con A capping and fMet-Leu-Phe- or Con A-mediated shape change were reduced in pertussis toxin-treated cells. Our results suggest that multiple mediators of inflammation act through a pertussis toxin-sensitive GTP-binding protein that regulates the mobilization of internal calcium as well as calcium uptake and is, in addition, a key control element of shape change, capping, and chemotaxis.
 ...
PMID:A pertussis toxin-sensitive GTP-binding protein in the human neutrophil regulates multiple receptors, calcium mobilization, and lectin-induced capping. 300 14

The effects of nonsteroidal anti-inflammatory agents on superoxide production and granule enzyme release by human polymorphonuclear leukocytes stimulated with either formyl-methionyl-leucyl-phenylalanine (fMet-Leu-Phe] or immune complexes were investigated. Cytochrome c reduction and the release of lysozyme, beta-glucuronidase, myeloperoxidase and gelatinase were measured. Auranofin, phenylbutazone, sulfasalazine and the phospholipase A2 inhibitor, 4-bromophenacyl bromide, strongly inhibited these responses in fMet-Leu-Phe stimulated cells, at concentrations below 50 microM. Indomethacin, piroxicam, mefenamic acid, primaquine and quinacrine at 50-250 microM were inhibitory. Up to 1 mM ibuprofen and chloroquine inhibited superoxide production but had little effect on degranulation. With cells stimulated by IgG aggregates (immune complexes), up to 1 mM ibuprofen, mefenamic acid and piroxicam did not inhibit either response. Indomethacin, phenylbutazone, sulfasalazine and primaquine inhibited, but considerably higher concentrations were required than with fMet-Leu-Phe. Quinacrine inhibited superoxide production equally well with both stimuli but inhibited enzyme release only with fMet-Leu-Phe. Only auranofin, 4-bromophenacyl bromide, and the weakly effective chloroquine exerted approximately the same effect with both stimuli. D-Penicillamine did not affect enzyme release with either stimulus and interfered in the superoxide assay. Gelatinase release induced by fMet-Leu-Phe was affected to the same extent, or slightly more, than release of the other granule enzymes. With immune complexes, there was only modest inhibition of gelatinase release by any of the drugs at 250-1000 microM. Our results reinforce previous observations that many anti-inflammatory drugs affect neutrophil functions, but their effects vary with stimulus. The relative insensitivity of immune complex-induced responses to most of the drugs must be taken into account when considering their mode of action.
 ...
PMID:Inhibition by nonsteroidal anti-inflammatory drugs of superoxide production and granule enzyme release by polymorphonuclear leukocytes stimulated with immune complexes or formyl-methionyl-leucyl-phenylalanine. 303 27

Human neutrophils can be permeabilized with the cholesterol complexing agent digitonin and then induced to secrete lysosomal constituents by increases in free Ca2+ alone. In order of increasing requirements for Ca2+, vitamin B-12 binding protein, lysozyme and beta-glucuronidase were released. A variety of guanine nucleotides were examined with respect to their abilities to modulate this response. GTP, along with its analogues 5'-guanylylimidodiphosphate (Gpp[NH]p) and guanosine-5'-O-[3-thio]-triphosphate (GTP[gamma S]) decreased the Ca2+ requirements for secretion of all three granule constituents by one third to one order of magnitude. This synergy was dependent upon the concentration of guanine nucleotides employed. The effects of Gpp[NH]p could be blocked with the inactive derivative GDP[beta-S]. The active guanine nucleotides, particularly GTP, served as stimuli in their own right. At high concentrations of Ca2+ and GTP, degranulation was strikingly inhibited; inhibition was also achieved with high concentrations of guanylyl[beta, gamma-methylene]diphosphate (Gpp[CH2]p). Both GDP and GMP were without any effect. When neutrophils were pretreated with pertussis toxin, granule discharge induced by fMet-Leu-Phe was almost completely blocked, as reported by others. If the neutrophils pretreated with pertussis toxin were then permeabilized with digitonin, the synergy between Ca2+ and the stimulatory guanine nucleotides was maintained. These data suggest the involvement of G-proteins in secretion induced by Ca2+; however, this response either uses a different G-protein or a different pool of G-proteins from those responses triggered by fMet-Leu-Phe.
 ...
PMID:Guanine nucleotides reduce the free calcium requirement for secretion of granule constituents from permeabilized human neutrophils. 353 3

The effect of some short-chain fatty acids (SCFA) produced by anaerobic bacteria, namely acetic, propionic, isobutyric, butyric, isovaleric and succinic acids, on production of light and release of lysozyme by human neutrophils exposed to chemotactic peptide fMet-Leu-Phe was investigated. A short period of incubation of neutrophils with SCFA led to marked inhibition of both granulocytic chemiluminescence and degranulation (P less than 0.001). Ultrastructural studies of neutrophils, incubated with concentrations of SCFA inhibiting the chemotactic response, chemiluminescence and release of lysozyme (30 mmol/l), effected alterations in cellular morphology with formation of protrusions of varying shape. The data reported indicate that SCFA might be regarded as important pathogenicity factors. The observed effect on neutrophils could also partially explain the ability of anaerobes to inhibit their own phagocytosis and killing as well as that of the aerobic species present in mixed infections.
 ...
PMID:Short-chain fatty acids produced by anaerobic bacteria alter the physiological responses of human neutrophils to chemotactic peptide. 381 57

Human neutrophils when exposed to appropriate stimuli aggregate, generate O(2) and secrete lysosomal constituents. To determine whether a causal relationship may exist between these responses neutrophils were exposed to either N-formyl-methionyl-leucyl-phenylalanine, phorbol myristate acetate, or the two calcium ionophores, A23187 and prostaglandin Bx. Each agent elicited all of the above responses. The concentrations required to elicit the aggregation of 30 . 10(6) neutrophils/ml were comparable to that required for O(2) generation or lysozyme release. In a series of experiments designed to dissociate these responses, cells were suspended in a concentration too dilute (3 . 10(6) neutrophils/ml) to permit aggregation to occur. O(2) generation and lysozyme release was measurable and varied in a dose-dependent fashion to the concentration of stimulus. In a second series of experiments, neutrophils were treated with 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid to inhibit degranulation without affecting O(2) generation. Aggregation was inhibited in a parallel fashion with lysozyme release. When detectable O(2) was removed from the medium by superoxide dismutase and catalase, aggregation and lysozyme release unaffected showing that aggregation can not be due to the presence of O(2) or its products in the extracellular medium. Neither aggregation of resting cells nor augmentation of fMet-Leu-Phe-induced aggregation was observed when cells were exposed to either supernatants of degranulated neutrophils or constituents of specific granules (lysozyme, lactoferrin). Kinetic analysis showed that in the absence of cytochalasin B degranulation preceded aggregation, while in its presence aggregation preceded degranulation.
 ...
PMID:The roles of degranulation and superoxide anion generation in neutrophil aggregation. 628 15


1 2 Next >>