Dexamethasone -induced apoptosis of human monocytes exposed to immune complexes. Intervention of CD95- and XIAP-dependent pathways.
Monocytes and macrophages play a key role in the initiation and persistence of inflammatory reactions. The possibility to interfere with the survival of these cells, once recruited and activated at sites of inflammation, is an attractive therapeutic option. Although resting monocytes are susceptible to pharmacologically induced apoptosis, no data are available about the possibility to modulate the survival of activated monocytes. The present work was planned to investigate if dexamethasone is able to promote apoptosis of human monocytes activated by immune complexes. When monocytes were cultured with immune complexes, a dose-dependent inhibition of apoptosis was observed. Dexamethasone stimulated apoptosis of resting and activated monocytes in a dose-dependent manner. Both the immune complex inhibitory activity and dexamethasone stimulatory properties depend on NF-kappaB/XIAP and Ras/MEK/ERK/CD95 pathways. In fact, the exposure of monocytes to immune complexes increased NF-kB activation and XIAP expression, which in turn were inhibited by dexamethasone. On the other hand, immune complex-stimulated monocytes displayed a reduced expression of CD95, which is prevented by dexamethasone, as well as by MEK inhibitor U0126. Furthermore, anti-CD95 ZB4 mAb prevented dexamethasone-induced apoptosis in immune complex stimulated monocytes. Similarly, ZB4 inhibited dexamethasone-mediated augmentation of caspase 3 activity. The present findings suggest that Fc triggering by insoluble immune complexes result in the activation of two intracellular pathways crucial for the survival of monocytes: 1. Ras/MEK/ERK pathway responsible for the down-regulation of CD95 expression; 2. NF-kappaB pathway governing the expression of XIAP. Both the pathways are susceptible to inhibition by monocyte treatment with pharmacologic concentrations of dexamethasone.
Ottonello
L
L
Laboratory of Phagocyte Physiopathology and Inflammation, Department of Internal Medicine, University of Genoa, Genoa, Italy. otto@unige.it
Bertolotto
M
M
Montecucco
F
F
Dapino
P
P
Dallegri
F
F
D000165:Acridine Orange / Q000378:metabolism; D000893:Anti-Inflammatory Agents / Q000378:metabolism / Q000494:pharmacology*; D000936:Antigen-Antibody Complex / Q000276:immunology; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D015153:Blotting, Western; D002478:Cells, Cultured; D003720:Densitometry; D003907:Dexamethasone / Q000378:metabolism / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D024202:Electrophoretic Mobility Shift Assay; D005434:Flow Cytometry; D019085:Fluorescent Antibody Technique, Direct; D006801:Humans; D009000:Monocytes / Q000187:drug effects / Q000276:immunology*; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000276:immunology*; D019014:fas Receptor / Q000276:immunology*
D000893:Anti-Inflammatory Agents; D000936:Antigen-Antibody Complex; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D019014:fas Receptor; D003907:Dexamethasone; D000165:Acridine Orange