Crystallographic and functional studies of a modified form of eosinophil-derived neurotoxin (EDN) with novel biological activities

Chang, Changsoo; Newton, Dianne L.; Rybak, Susanna M.; Wlodawer, Alexander

doi:10.1006/jmbi.2002.5406

Cited by 8 publications

(4 citation statements)

References 39 publications

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“…Although the Ϫ4 form of EDN was used in our study, it is highly possible that EDN without the N-terminal 4 additional residues may also be chemotactic since both forms have essentially identical tertiary structures. 18,42 Additional support for this notion comes from the fact that, mEAR2, which lacks the corresponding N-terminal 8 residues of Ϫ4 form of EDN ( Figure 5A), is nevertheless similarly chemotactic as the Ϫ4 form of EDN. Sequence comparison of EDN and mEAR2 (chemotactic for DCs), and hANG and hPR (not chemotactic for DCs) and remarkably decreased DC chemotactic activity of the hPR/mEAR2 chimera indicate that the N-terminal region ( 1 Q-9 I) of mEAR2 is important for its DC chemotactic activity ( Figure 5).…”

Section: Discussionmentioning

confidence: 91%

Eosinophil-derived neurotoxin (EDN), an antimicrobial protein with chemotactic activities for dendritic cells

Yang

Rosenberg

Chen

et al. 2003

Blood

144

134

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IntroductionAntimicrobial proteins of neutrophil granules have long been considered as important elements of innate host defense. 1 In recent years, evidence has been accumulating indicating that some neutrophil granule-derived antimicrobial proteins also act as chemoattractants for various types of leukocytes. For example, neutrophil-derived ␣-defensins have been shown to be chemotactic for human monocytes, T cells, and immature dendritic cells (iDCs). [2][3][4] Azurocidin and cathelicidins, 2 antimicrobial proteins predominantly stored in neutrophil granules, are chemotactic for neutrophils, monocytes, T cells, and mast cells. 3,[5][6][7][8][9] Cathepsin G, on the other hand, is chemotactic for neutrophils and monocytes. 5 Furthermore, in mouse experimental models, neutrophil granulederived defensins are capable of enhancing antigen-specific immune responses when administered simultaneously with antigens. 10,11 Thus, these neutrophil granule-derived antimicrobial proteins have the capacity to participate in mobilizing and amplifying adaptive immunity by functioning as leukocyte chemoattactants and/or activators. 12 In addition to neutrophil granule-derived antimicrobial proteins, chymase, a serine protease found in the granules of basophils and mast cells, has been shown to induce neutrophil and monocyte chemotaxis. 13 Human eosinophil granules contain several antimicrobial proteins including eosinophil-derived neurotoxin (EDN), 14,15 which together with eosinophil cationic protein belongs to what has come to be recognized as the RNase A superfamily. 16 EDN was purified in 1981 14 and its gene was cloned in 1989. 17 Its 3-dimensional structure has also been solved by X-ray crystallography. 18 Aside from its neurotoxic effect, 14 EDN has been shown to have antiviral activity, in particular against respiratory syncytial virus in vitro, 19,20 suggesting that EDN may contribute to host antiviral defense against single-strand RNA viruses. 21 Very recently, EDN has also been shown to be responsible in part for the HIV-1 inhibitory activities in the supernatant of allogeneic mixed lymphocyte reaction. 22 However, it is not known whether EDN, like several other antimicrobial proteins derived from the granules of neutrophils and basophils/mast cells, may also have chemotactic activity for leukocytes. To test this possibility, we have investigated the capacity of EDN to induce the migration of various types of human leukocytes and found that EDN and its divergent mouse ortholog, mouse eosinophil-associated RNase 2 (mEAR2), 23 can act as selective chemoattractants for DCs. Materials and methods ReagentsRecombinant human (rh) stromal cell-derived factor-1␣ (SDF-1␣), tumor necrosis factor ␣ (TNF␣), granulocyte-macrophage colony-stimulating The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. The publisher or recipient acknowledges right ...

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Section: Discussionmentioning

confidence: 91%

Eosinophil-derived neurotoxin (EDN), an antimicrobial protein with chemotactic activities for dendritic cells

Yang

Rosenberg

Chen

et al. 2003

Blood

144

134

View full text Add to dashboard Cite

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“…This eosinophil protein has been described for its tumoricidal effect (46)(47)(48)(49) and pore membrane-forming properties (50,51). A recent study showed that ECP was not internalized (52).…”

Section: Discussionmentioning

confidence: 99%

Human Eosinophils Exert TNF-α and Granzyme A-Mediated Tumoricidal Activity toward Colon Carcinoma Cells

Legrand

Driss

Delbeke

et al. 2010

The Journal of Immunology

144

135

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Peripheral blood and tissue eosinophilia is a prominent feature in allergic diseases and helminth infections. In cancer patients, tumor-associated tissue eosinophilia is frequently observed. Tumor-associated tissue eosinophilia can be associated with a favorable prognosis, notably in colorectal carcinoma. However, underlying mechanisms of eosinophil contribution to antitumor responses are poorly understood. We have in this study investigated the direct interactions of human eosinophils with Colo-205, a colorectal carcinoma cell line, and show that eosinophils induce apoptosis and directly kill tumor cells. Using blocking Abs, we found that CD11a/CD18 complex is involved in the tumoricidal activity. Coculture of eosinophils with Colo-205 led to the release of eosinophil cationic protein and eosinophil-derived neurotoxin as well as TNF-α secretion. Moreover, eosinophils expressed granzyme A, which was released upon interaction with Colo-205, whereas cytotoxicity was partially inhibited by FUT-175, an inhibitor of trypsin-like enzymatic activity. Our data present the first demonstration, to our knowledge, that granzyme A is a cytotoxic mediator of the eosinophil protein arsenal, exerting eosinophil tumoricidal activity toward Colo-205, and provide mechanistic evidence for innate responses of eosinophil against tumor cells.

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“…An additional disulfide bond (Cys87–Cys104) found only in frog RNases is important for onconase cytotoxicity [31]. Two naturally existing forms of eosinophil‐derived neurotoxin (EDN) have identical structures, but only (−4)EDN markedly inhibits the viability of Kaposi's sarcoma cells [5,32].…”

Section: Killer's Image: Structurementioning

confidence: 99%

Cytotoxic ribonucleases: molecular weapons and their targets

2003

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Many ribonucleases (RNases) are highly cytotoxic. In some cases, they attack selectively malignant cells, triggering apoptotic response, and therefore are considered as alternative chemotherapeutic drugs. Factors that determine the cytotoxicity of RNases, primarily of those of microbial origin, are reviewed here. These factors include catalytic activity, ability to escape natural inhibitors, stability, and e⁄ciency of internalization. The latter is, in turn, determined by positive charge on the molecule and interaction with cell membrane. Cellular targets and molecular determinants of RNases decisive for their cytotoxic action are characterized.

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Crystallographic and functional studies of a modified form of eosinophil-derived neurotoxin (EDN) with novel biological activities

Cited by 8 publications

References 39 publications

Eosinophil-derived neurotoxin (EDN), an antimicrobial protein with chemotactic activities for dendritic cells

Eosinophil-derived neurotoxin (EDN), an antimicrobial protein with chemotactic activities for dendritic cells

Human Eosinophils Exert TNF-α and Granzyme A-Mediated Tumoricidal Activity toward Colon Carcinoma Cells

Cytotoxic ribonucleases: molecular weapons and their targets

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