Published online before print August 9, 2007

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(American Journal of Pathology. 2007;171:928-937.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.061043

Neutrophil Elastase Converts Human Immature Dendritic Cells into Transforming Growth Factor-ß1-Secreting Cells and Reduces Allostimulatory Ability

Paulo César Maffia^*, Sandra Elizabeth Zittermann^*, María Lucila Scimone^*, Nancy Tateosian^*, Nicolás Amiano^*, Diego Guerrieri^*, Viviana Lutzky^*, Diego Rosso, Horacio Eduardo Romeo, Verónica E. Garcia^*, Andrew C. Issekutz and H. Eduardo Chuluyan^*

From the Lanais de la Facultad de Medicina,^* and Sección Hematología y Oncología, Departamento de Pediatría, Hospital de Clínicas "José de San Martín," Facultad de Medicina, y Departamento de Farmacología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina; the Department of Pediatrics, Dalhousie University, Halifax, Nova Scotia, Canada; and the Department of Neurobiology, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California

During microbial infection, neutrophils (polymorphonuclear leukocytes; PMNs) activate dendritic cells (DCs). However, early reports illustrated that neutrophil-derived mediators may suppress responses to mitogens. In the present study, we investigated the mechanism used by PMNs to modulate the immunostimulatory ability of DCs. Autologous syngeneic PMNs decreased T-cell proliferation induced by allogeneic DCs. Culture supernatant (CS) derived from PMNs also decreased allostimulation ability of immature DCs and increased the expression of transforming growth factor (TGF)-ß1 on DCs. A TGF-ß1 monoclonal antibody, a CD40 monoclonal antibody, or a serine protease inhibitor reversed the effect of PMN CS on DC allostimulatory ability. Furthermore, elastase reproduced the inhibitory effect of PMN CS on DC allostimulatory ability and the TGF-ß1 production. The role of elastase was confirmed by examining PMN CS from two patients with cyclic neutropenia, a disease due to mutations in the neutrophil elastase gene. These PMN CS samples had reduced elastase activity and were unable to increase DC TGF-ß1 production. Moreover, elastase and PMN CS induced IB degradation in DCs. We conclude that PMNs decrease DC allostimulatory ability via production of elastase leading to a switch of immature DCs into TGF-ß1-secreting cells.

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