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Published online before print October 21, 2005
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* Department of Pathology, Division of General Pathology, University of Verona, Italy;
Unit of Immunotherapy of Human Tumors, Istituto Nazionale Tumori, Milano, Italy;
Istituto di Ricerche Farmacologiche Mario Negri, Milano and Istituto Clinico Humanitas, Rozzano, Italy; and
Division of Hematology, Ospedale Regionale Cà Foncello, Treviso, Italy
1 Correspondence: Department of Pathology, Section of General Pathology, University of Verona, Strada Le Grazie 4, 37134 Verona, Italy. E-mail: marco.cassatella{at}univr.it
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-
, 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.
Key Words: T lymphocyte • LPS • fMLP • CXCL
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