A mechanism for neutrophil-mediated lysis of human neuroblastoma cells.
Neutrophils mediate the lysis of human neuroblastoma cells coated with human/mouse chimeric anti-GD2 ganglioside antibody ch14.18. This study examined the mechanism(s) by which this occurs. Neutrophil degranulation was found to be a required step for lysis, since release of granular enzymes from neutrophils correlated with the lysis of antibody-coated neuroblastoma cells. In addition, agents which block degranulation specifically inhibited this process. Antibody-dependent lysis of neuroblastoma cells was enhanced by exposing neutrophils to granulocyte-macrophage colony stimulatory factor. An increased release of lytic granular molecules was found to be responsible for this lymphokine-mediated phenomenon. Among the molecules released from neutrophil granules that were shown to be involved in neuroblastoma cell lysis were defensins, M(r) 3000-4000 neutrophil granular proteins which are known to bind and permeabilize tumor cells. In addition, cathepsin-G, a neutrophil granular protease, was demonstrated for the first time to mediate the lysis of human neuroblastoma cells. The enzymatic activity of cathepsin-G was found to be required for the lysis of these tumor cells, since phenylmethylsulfonyl fluoride blocks the lytic ability of this protein.
Barker
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Department of Immunology, Scripps Research Institute, La Jolla, California 92037.
Reisfeld
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RA
D000912:Antibodies, Neoplasm / Q000276:immunology; D000920:Antibody-Dependent Cell Cytotoxicity; D001798:Blood Proteins / Q000494:pharmacology; D056649:Cathepsin G; D002403:Cathepsins / Q000494:pharmacology; D015550:Cell Degranulation; D003602:Cytotoxicity, Immunologic; D023082:Defensins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D009447:Neuroblastoma / Q000276:immunology*; D009504:Neutrophils / Q000276:immunology*; D010196:Pancreatic Elastase / Q000494:pharmacology; D012697:Serine Endopeptidases; D014407:Tumor Cells, Cultured
D000912:Antibodies, Neoplasm; D001798:Blood Proteins; D023082:Defensins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D002403:Cathepsins; D012697:Serine Endopeptidases; C534094:CTSG protein, human; D056649:Cathepsin G; C534096:Ctsg protein, mouse; D010196:Pancreatic Elastase