Neutral endopeptidase 24.11 in human neutrophils: cleavage of chemotactic peptide.

Connelly, Jon C.; Skidgel, Randal A.; Schulz, Werner; Johnson, Alice; Erdös, Ervin G.

doi:10.1073/pnas.82.24.8737

Cited by 156 publications

(101 citation statements)

References 25 publications

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“…Incubation of unlabelled ET-1 with purified cathepsin G allowed to identify a major cleavage site corresponding to the Hisl6-Leu x7 bond, leading to the formation of inactive [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16] fragments and the C-terminal pentapeptide.…”

Section: Discussionmentioning

confidence: 99%

“…This neutral metallo-endopeptidase, identical with the 'common acute lymphoblastic leukemia antigen' [ 16], is located on the cell membrane of neutrophils where it is involved in the breakdown of fMet-Leu-Phe, the major chemotactic peptide produced by Escherichia Coli [12]. Inhibition of the enzyme completely blocks fMLP-mediated chemotaxis [17].…”

Section: Discussionmentioning

confidence: 99%

“…5). They were collected and submitted to amino acid analysis, Peaks 1, 2, 3 had amino acid compositions compatible with the sequence ET-1 [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16] and probably differed from each other by additional cleavages in the disulfidelinked loops (Table I) had a composition identical to that of ET-1 and might differ from the intact substrate by one or more cleavages inside the disulfide-linked loops. Peak 6 was present as a double peak due to the appearance of a metabolite not resolved from ET-1.…”

Section: Hydrolysis Of Unlabelled Et-1 By Cathepsin Gmentioning

confidence: 99%

“…Considering the presence of endopeptidase 24.11 at the surface of polymorphonuclear neutrophils (PMN) [12], we investigated whether this enzyme was able to hydrolyze ET-1 in an in vitro cellular system. Resting and phorbol 12-myristate 13-acetate (PMA) activated PMN were incubated with 125I-labelled ET-1, and the degradation fragments were analyzed by HPLC.…”

Section: Introductionmentioning

confidence: 99%

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Enzymatic degradation of endothelin-1 by activated human polymorphonuclear neutrophils

Fagny¹,

Michel²,

Nortier³

et al. 1992

Regulatory Peptides

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SummaryEndothelin-1 (ET-1) is a potent vasoconstrictor peptide secreted by endothelial cells. We investigated whether polymorphonuclear neutrophils (PMN) were able to destroy this peptide by enzymatic hydrolysis produced either by the membrane-bound endopeptidase 24.11 or by lysosomal proteinases released in the medium by activated cells. Resting and activated PMN were incubated with 125I-labelled ET-1 and the degradation fragments were analyzed by HPLC. A marked degradation of ET-1 was observed only in the presence of the stimulated cells, leading to the generation of seven radiolabelled peaks. Addition of phosphoramidon had no effect on the appearance of these metabolites, while soybean trypsin inhibitor abolished almost completely the degradation of the peptide, suggesting a role of cathepsin G in ET-1 hydrolysis.Among the purified leukocyte enzymes tested, cathepsin G hydrolyzed 125I-labelled ET-1 at the higher rate and gave rise to two radiolabelled peaks already observed in the presence of activated PMN. Incubation of unlabelled ET-1 with purified cathepsin G allowed to identify a major cleavage site corresponding to the Hisl6-Leu x7 bond, leading to the formation of inactive [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16] fragments and the C-terminal pentapeptide.This mechanism of ET-1 inactivation could play a role in acute inflammatory reaction where PMN adhere to the vascular endothelial cells.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Hydrolysis Of Unlabelled Et-1 By Cathepsin Gmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Enzymatic degradation of endothelin-1 by activated human polymorphonuclear neutrophils

Fagny¹,

Michel²,

Nortier³

et al. 1992

Regulatory Peptides

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“…Neutrophils have been found in atherectomy specimens in patients with unstable angina. There is supporting evidence 29,30 that neutrophils are activated in eroded plaques, likewise as in the inflammatory state, thus suggesting a probable contribution to the pathogenesis of ACS.…”

Section: Discussionmentioning

confidence: 77%

Neutrophil Count on Admission Predicts Major In‐hospital Events in Patients with a Non‐ST‐Segment Elevation Acute Coronary Syndrome

Karabinos

Koulouris

Kranidis

et al. 2009

Clinical Cardiology

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Background: Inflammation plays a key role in the pathogenesis of acute coronary syndromes (ACS). In this context we assessed neutrophil count as a predictor of major in-hospital events in patients admitted for a non-ST-segment elevation (NSTE) ACS. Methods: We measured neutrophils on admission in 160 patients with a NSTE ACS and we correlated their count with the incidence of a combined in-hospital end point including: cardiac death, acute heart failure, ST-segment elevation myocardial infarction, and recurrent myocardial ischemia. Results: Patients who had a major in-hospital event also had a higher neutrophil count (P = 0.02) and higher serum levels of troponin I (P = 0.04). In the univariate logistic regression analysis, in-hospital major events could be predicted by troponin I >0.07 ng/mL (odds ratio [OR]: 5.65, 95% confidence interval [CI]: 1.26-25.32, P = 0.02), white blood cell count >8650 cells/µL (OR: 2.68, 95% CI: 1.03-6.95, P = 0.04), neutrophil count >6700 cells/µL (OR: 7.74, 95% CI: 2.79-21.47, P < 0.001), and C-reactive protein >0.97 mg/dL (OR: 3.56, 95% CI: 1.13-11.19, P = 0.02). However, in multivariate regression, neutrophil count >6700 cells/µL (OR: 6.52, 95% CI: 1.56-27.22, P = 0.01) was the only independent in-hospital prognostic factor. Conclusions: In patients with a NSTE ACS of moderate or high risk, neutrophil count on admission may identify those who are at risk of having an adverse in-hospital outcome.

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Enkephalinase: A physiologic neuroimmunomodulator detected in the synovial fluid

Appelboom

Maertelaer²,

Prez³

et al. 1991

Arthritis & Rheumatism

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Enkephalinase (endopeptidase 24.11) is a metallopeptidase that is able to cleave not only neuropeptides and hormones but also immune mediators. The enzyme was quantified in synovial fluid obtained from 36 swollen joints. Its concentration correlated with the synovial fluid cell count, mainly the polymorphonuclear cells and lymphocytes, and with the erythrocyte sedimentation rate. No statistically significant difference in enkephalinase levels was demonstrated between the groups of patients with rheumatoid arthritis, seronegative spondylarthropathy, microcrystalline arthritis, or osteoarthritis. The presence of enkephalinase in the synovial fluid could reflect the intensity of the inflammatory process, or it could represent a physiologic regulator of inflammation and pain within the joint. cleaving not only enkephalins but also a series of other peptides and hormones, such as the chemotactic peptide FMLP, substance P, neurotensin, glucagon, cholecystokinin octapeptide, gastrin, and atrial natriuretic peptide. It is anchored in the plasma lipid membrane bilayer of many normal cell types and tissues (e.g., brain, lung, kidney, bone, thyroid, salivary glands) (1).Although the enzyme is primarily a membranebound protein, a soluble form has been identified in serum and has been shown to be increased in patients with sarcoidosis (2), adult respiratory distress syndrome (3), and end-stage renal failure (4). The cellular origin of this circulating enkephalinase remains unknown. In view of the strong circumstantial evidence implicating substrates of enkephalinase in the local neurogenic mechanism for arthritis (3, enkephalinase appears potentially capable of modulating pain, inflammation, and the biological responses to various hormones and cytokines in the joint.The present study was undertaken to determine whether enkephalinase could be detected in the joints of patients with various clinical forms of arthritis, and consequently, which parameters influence the concentration of this enzyme.Patients and methods. Thirty-six patients (mean * SD age 56.4 -+ 13.4; ma1e:female ratio 0 . Q each of whom had a swollen knee, were included in this study. The diagnoses were as follows: rheumatoid arthritis (n = 13), microcrystalline arthritis (n = lo), seronegative spondylarthropathy (n = 7), and osteoarthritis (n = 6). Synovial fluid was aspirated from the knee joints and immediately analyzed for the presence of crystals and cell count. Blood samples were also obtained for analysis, which included the erythrocyte sedimenta-

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Neutral endopeptidase 24.11 in human neutrophils: cleavage of chemotactic peptide.

Cited by 156 publications

References 25 publications

Enzymatic degradation of endothelin-1 by activated human polymorphonuclear neutrophils

Enzymatic degradation of endothelin-1 by activated human polymorphonuclear neutrophils

Neutrophil Count on Admission Predicts Major In‐hospital Events in Patients with a Non‐ST‐Segment Elevation Acute Coronary Syndrome

Enkephalinase: A physiologic neuroimmunomodulator detected in the synovial fluid

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