Neutrophil elastase converts human immature dendritic cells into transforming growth factor-beta1-secreting cells and reduces allostimulatory ability.
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.
Maffia
Paulo César
PC
Lanais de la Facultad de Medicina, Universidad de Buenos Aires, Avenida Córdoba 2351, C.P. 1120, Buenos Aires, Argentina.
Zittermann
Sandra Elizabeth
SE
Scimone
María Lucila
ML
Tateosian
Nancy
N
Amiano
Nicolás
N
Guerrieri
Diego
D
Lutzky
Viviana
V
Rosso
Diego
D
Romeo
Horacio Eduardo
HE
Garcia
Verónica E
VE
Issekutz
Andrew C
AC
Chuluyan
H Eduardo
HE
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*
D017077:Culture Media, Conditioned; D053773:Transforming Growth Factor beta1; D019272:Leukocyte Elastase
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