Identification of elastases associated with purified plasma membranes isolated from human monocytes and lymphocytes

Fuks, Alejandro; Zucker‐Franklin, Dorothea; Franklin, Edward C.

doi:10.1016/0304-4165(83)90203-9

Cited by 19 publications

(6 citation statements)

References 32 publications

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“…Thus, it has been shown that 5' nucleotidase activity becomes reduced when peritoneal macrophages are stimulated (38,39), and a decrease in receptors after binding and internalization of ligands has been observed in several systems (e.g., 40). We have shown for monocytes that degradation of SAA is surface membrane associated (5,7,22). It is likely that the same holds true for KC, especially since SAA degradation also required the continuous presence of the cells.…”

Section: M P a I R E D K U P F F E R Cell F U N C T I O N Precedes mentioning

confidence: 52%

“…The culture medium of control KC was also incubated with SAA to determine whether the relevant proteolytic activity is secreted or whether, as in the case of monocytes, it remains intimately associated with cells. In addition, the KC as well as the medium were incubated separately with orcein-impregnated elastin (Sigma Chemical Co.) to assay for elastase-like enzymes as described previously (21,22).…”

Section: Methodsmentioning

confidence: 99%

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Impaired Kupffer cell function precedes development of secondary amyloidosis.

Fuks¹,

Zucker‐Franklin²

1985

The Journal of Experimental Medicine

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It has been demonstrated previously that the acute phase reactant, serum amyloid A (SAA), is subject to degradation by surface membrane-associated proteinases of peripheral blood monocytes. However, monocytes obtained from the blood of patients with amyloidosis degraded SAA incompletely, leaving a cleavage product that, biochemically and immunologically, resembled the amyloid protein A (AA) deposited in their tissues. To investigate the role of fixed macrophages in amyloidogenesis and to establish more definitively that amyloid deposition is attributable to faulty processing of the precursor protein rather than aberrant synthesis, secondary amyloidosis was induced in C57BL/6J mice by serial injections of casein. Kupffer cells (KC) were isolated from livers of mice that had received 0, 8, 13, 18, and greater than 30 injections of the stimulant. The cells were cultured with SAA for 4, 8, and 18 h and then subjected to electron microscopy and enzyme analyses. The medium was analyzed by SDS-PAGE to determine the amount of residual SAA and/or the appearance of AA. KC of healthy animals degraded SAA completely whereas KC of stimulated mice showed increasing amounts of residual SAA and the appearance of the AA cleavage product. The AA peptide appeared in KC cultures early during the course of casein injections and before any amyloid could be demonstrated in the organs of the stimulated mice. The addition of KC isolated from healthy mice to cultures that had produced AA eliminated the abnormal peptide. The results, indicate that defective KC function precedes amyloidosis. The abnormal AA cleavage product formed by such cells is still susceptible to hydrolysis by normal cells. In addition, ultrastructural evidence is presented that suggests that KC may also play a role in fibrillogenesis of the AA protein.

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Section: M P a I R E D K U P F F E R Cell F U N C T I O N Precedes mentioning

confidence: 52%

Section: Methodsmentioning

confidence: 99%

Impaired Kupffer cell function precedes development of secondary amyloidosis.

Fuks¹,

Zucker‐Franklin²

1985

The Journal of Experimental Medicine

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“…At least part of this activity appears to be explained by neutrophil elastase on or within macrophages or by neutrophils contaminating the macrophage preparations (30). However, recently reported studies indicate that human monocytes express a membrane-bound elastase and that human monocyte-derived macrophages contain an elastase that is not neutrophil elastase (31,32). Most assays of elastase activity utilize a detergent-treated elastin and, therefore, assay either lysed cells or conditioned medium from cultured cells (20,30,33,34 elastin-only matrices in the presence ofplg (Table III).…”

Section: Resultsmentioning

confidence: 99%

Degradation of fibrin and elastin by intact human alveolar macrophages in vitro. Characterization of a plasminogen activator and its role in matrix degradation.

Chapman¹,

Stone²,

Vavrin³

1984

J. Clin. Invest.

160

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fibrin. Live macrophages also degraded insoluble elastin only when in contact with the elastin but could do so even in the presence of serum proteinase inhibitors. In matrices containing a mixture of fibrin and elastin, cells did not degrade elastin unless plasminogen was added to the medium. These results indicate that normal alveolar macrophages synthesize and express, probably at the cell surface, a PA. The PA is physically and immunochemically similar to urokinase but is membrane bound. The PA is critical to the degradation of fibrin matrices by normal alveolar macrophages. Under tissue conditions where elastin is embedded within other structural proteins, the activator may be rate-limiting in elastin degradation as well. The findings also suggest that live macrophage proteolytic activity is relatively insensitive to the presence of serum proteinase inhibitors, suggesting a mechanism for proteolytic lung injury even in the presence of proteinase-proteinase inhibitor balance in the soluble phase.

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“…First, NE undergoes regulated secretion and would be at locally high concentrations in the extracellular environment of the bone marrow. Second, biochemical and immunolocalization studies show that in addition to granules, NE also appears on the plasma membrane and cleaves transmembrane receptors (1,10,11,17,25,34). Third, endocytosis of Notch also contributes to Notch regulation (8,38), and NE is present in endocytically derived granules.…”

Section: Discussionmentioning

confidence: 99%

A Novel Notch Protein, N2N, Targeted by Neutrophil Elastase and Implicated in Hereditary Neutropenia

Duan

Wechsler

et al. 2004

Molecular and Cellular Biology

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Mutations in ELA2, encoding the human serine protease neutrophil elastase, cause cyclic and severe congenital neutropenia, and recent evidence indicates that the mutations alter the membrane trafficking of neutrophil elastase. These disorders feature impaired bone marrow production of neutrophils along with excess monocytes-terminally differentiated lineages corresponding to the two alternative fates of myeloid progenitor cells. We utilized a modified yeast two-hybrid system and identified a new, widely expressed gene, N2N, whose product is homologous to Notch2, that interacts with neutrophil elastase. N2N is a 36-kDa protein distributed throughout the cell and secreted. Its amino-terminal sequence consists of several EGF repeats identical to those of the extracellular region of Notch2, and its carboxyl terminus contains a unique 24-residue domain required for interaction with neutrophil elastase. Neutrophil elastase cleaves N2N within EGF repeats in vitro and in living cells, but the C-terminal domain retards proteolysis. In vitro, N2N represses transcriptional activities of Notch proteins. Disease-causing mutations of neutrophil elastase disrupt the interaction with N2N, impair proteolysis of N2N and Notch2, and interfere with Notch2 signaling, suggesting defective proteolysis of an inhibitory form of Notch as an explanation for the alternate switching of cell fates characteristic of hereditary neutropenia.Neutrophils are phagocytic white blood cells that serve as a first line of defense against bacterial and fungal infection and coordinate inflammatory responses. The surprising finding that mutation of the gene ELA2, encoding neutrophil elastase (NE), is responsible for inherited forms of human neutropenia indicates that this serine protease, primarily found in granules of neutrophils and monocytes, plays an unexpected role in the regulation of hematopoietic stem cell differentiation. The two major forms of human hereditary neutropenia are cyclic neutropenia (CN), characterized by 21-day sinusoidal oscillations in neutrophil production, and severe congenital neutropenia (SCN), comprised of arrested promyelocytic differentiation frequently progressing to myelodysplasia and acute myelogenous leukemia. CN is always (22), and SCN usually (2, 12), the result of autosomal dominant, heterozygous ELA2 mutations.To date, a total of more than two dozen mutant NE proteins have been reported (21). However, the role of the mutations in the pathophysiology of these disorders and NE's normal function in myeloid differentiation remain unclear. The mutations have variable effects on overall catalytic activity and are not cytotoxic (28). The recent finding that the mutations do affect the subcellular localization of NE (6), and, in particular, their membrane trafficking, suggests the possibility of defective interactions between mutant NE and membrane proteins.Additionally, two clinical clues suggest how NE might contribute to myelopoiesis. First, it appears that neutropenia results from an aberrant switch in cell fate. A stri...

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Identification of elastases associated with purified plasma membranes isolated from human monocytes and lymphocytes

Cited by 19 publications

References 32 publications

Impaired Kupffer cell function precedes development of secondary amyloidosis.

Impaired Kupffer cell function precedes development of secondary amyloidosis.

Degradation of fibrin and elastin by intact human alveolar macrophages in vitro. Characterization of a plasminogen activator and its role in matrix degradation.

A Novel Notch Protein, N2N, Targeted by Neutrophil Elastase and Implicated in Hereditary Neutropenia

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