Neutrophil elatase converts immature dendritic cells into TGF-ƒÒ secreting cells and reduces allostimulatory ability.

MAFFIA PAULO; ZITTERMANN SANDRA; SCIMONE LUCILA; TATEOSIAN NANCY; AMIANO NICOLAS; GUERRIERI DIEGO; LUTZKY VIVIANA; ROSSO DIEGO; ROMEO HORACIO; GARCÍA VERÓNICA; ISSEKUTZ ANDREW; CHULUYAN EDUARDO

AMERICAN JOURNAL OF PATHOLOGY

AMER SOC INVESTIGATIVE PATHOLOGY, INC

Año: 2007 vol. 171 p. 928 - 937

0002-9440

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.