title: Neutrophil elastase converts human immature dendritic cells into transforming growth factor-beta1-secreting cells and reduces allostimulatory ability.
abstract: 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)-beta1 on DCs. A TGF-beta1 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-beta1 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-beta1 production. Moreover, elastase and PMN CS induced IkappaBalpha degradation in DCs. We conclude that PMNs decrease DC allostimulatory ability via production of elastase leading to a switch of immature DCs into TGF-beta1-secreting cells.
authors: Lanais de la Facultad de Medicina, Universidad de Buenos Aires, Avenida Córdoba 2351, C.P. 1120, Buenos Aires, Argentina.
authors: Paulo César
authors: PC
authors: Maffia
authors: Sandra Elizabeth
authors: SE
authors: Zittermann
authors: María Lucila
authors: ML
authors: Scimone
authors: Nancy
authors: N
authors: Tateosian
authors: Nicolás
authors: N
authors: Amiano
authors: Diego
authors: D
authors: Guerrieri
authors: Viviana
authors: V
authors: Lutzky
authors: Diego
authors: D
authors: Rosso
authors: Horacio Eduardo
authors: HE
authors: Romeo
authors: Verónica E
authors: VE
authors: Garcia
authors: Andrew C
authors: AC
authors: Issekutz
authors: H Eduardo
authors: HE
authors: Chuluyan
mesh_terms: D000293:Adolescent; D000328:Adult; D000494:Allosteric Regulation; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D005260:Female; D006801:Humans; D019272:Leukocyte Elastase / Q000378:metabolism*; D008297:Male; D009504:Neutrophils / Q000166:cytology / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*
chemical_list: D017077:Culture Media, Conditioned; D053773:Transforming Growth Factor beta1; D019272:Leukocyte Elastase
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