Interferon-activated neutrophils store a TNF-related apoptosis-inducing ligand (TRAIL/Apo-2 ligand) intracellular pool that is readily mobilizable following exposure to proinflammatory mediators.
Neutrophils are versatile cells, which play a role, not only in inflammatory processes but also in immune and antitumoral responses. Recently, we have reported that interferon (IFN)-activated neutrophils are able to release biologically active tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL/APO2 ligand), a molecule exerting selective, apoptotic activities toward tumor and virus-infected cells, as well as immunoregulatory functions on activated T lymphocytes. Herein, we show that only a minor fraction of the total TRAIL, newly synthesized by IFN-activated neutrophils within 24 h, is released outside, the rest being retained intracellularly, mainly in secretory vesicles and light membrane fractions. We demonstrate that the intracellular pool of TRAIL present in IFN-pretreated neutrophils is rapidly mobilizable to the cell surface and can be secreted following exposure to proinflammatory mediators such as TNF-alpha, lipopolysaccharide, formyl-methionyl-leucyl-phenylalanine, CXC chemokine ligand 8/interleukin-8, insoluble immunocomplexes, and heat shock protein Gp96. These various proinflammatory agonists functioned as effective secretagogue molecules only, in that they failed to augment TRAIL mRNA expression or TRAIL de novo synthesis in freshly isolated neutrophils or cultured with or without IFN. In addition, supernatants from IFN-treated neutrophils stimulated with proinflammatory mediators induced the apoptosis of target cells more effectively than supernatants from neutrophils activated with IFNs alone. Collectively, our results uncover a novel mechanism, whereby the release of soluble TRAIL by neutrophils can be greatly amplified and further reinforce the notion that neutrophils are important cells in tumor surveillance and immunomodulation.
Cassatella
Marco A
MA
Division of General Pathology, Department of Pathology, University of Verona, Itlay. marco.cassatella@univr.it
Huber
Veronica
V
Calzetti
Federica
F
Margotto
Daniela
D
Tamassia
Nicola
N
Peri
Giuseppe
G
Mantovani
Alberto
A
Rivoltini
Licia
L
Tecchio
Cristina
C
D000936:Antigen-Antibody Complex / Q000494:pharmacology; D051017:Apoptosis Regulatory Proteins / Q000276:immunology / Q000378:metabolism*; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology; D004357:Drug Synergism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D007157:Immunologic Surveillance / Q000187:drug effects / Q000276:immunology; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009369:Neoplasms / Q000276:immunology / Q000473:pathology; D018375:Neutrophil Activation / Q000187:drug effects / Q000276:immunology*; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D014176:Protein Biosynthesis / Q000187:drug effects / Q000276:immunology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000276:immunology; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism*
D000936:Antigen-Antibody Complex; D051017:Apoptosis Regulatory Proteins; D016207:Cytokines; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; C053387:endoplasmin; D009240:N-Formylmethionine Leucyl-Phenylalanine