Immune complexes induce monocyte survival through defined intracellular pathways.
Monocytes recruitment and survival at sites of inflammation are determinant for the persistence of inflammatory reactions. Immune-complexes (ICs), whose tissue deposition is involved in a variety of autoimmune diseases, activate monocytes through the interaction with Fcgamma-receptor triggering the secretion of several inflammatory modulators and favoring their tissue accumulation by inhibiting the apoptosis. To elucidate the intracellular pathways governing this process, on the basis of our previous findings regarding the dose-dependent inhibition of apoptosis in IC-activated monocytes, we have investigated the role of PI3K/Akt pathway, MAP kinases, nuclear factor-kappaB (NF-kappaB), and caspase 3, 8, and 9. Here we show that IC-activated monocytes underwent apoptosis at a rate comparable to that of resting monocytes in the presence of LY294002, a selective inhibitor of PI3K, as well in the presence of Akt inhibitor, PD98059 inhibitor of ERK1/2, and SB203580 inhibitor of p38. Moreover, IC-triggered phosphorylation of Akt, ERK1/2, and p38 MAP kinase was demonstrated on Western blot analysis. SN50, an inhibitor of NF-kappaB translocation and BMS345541, a specific inhibitor of IKK, also abolished the apoptosis protection conferred by ICs. In parallel, ICs induced an increase in NF-kappaB activation, as shown by EMSA, together with the expression of XIAP, as shown by Western blot, though indicating that in monocytes IC protection from apoptosis is NF-kappaB dependent. Finally, the activity of caspase 3, 8, and 9 resulted inhibited in IC-activated monocytes. These results disclose a signaling route triggered by ICs which can be involved in the pathophysiology of inflammatory diseases and can represent a target for therapy of IC-mediated diseases.
Bianchi
Giordano
G
Dipartimento di Medicina Interna e Specialita' Mediche, Viale Benedetto XV n. 6, 16132 Genova, Italy.
Montecucco
Fabrizio
F
Bertolotto
Maria
M
Dallegri
Franco
F
Ottonello
Luciano
L
D000936:Antigen-Antibody Complex / Q000502:physiology*; D017209:Apoptosis / Q000276:immunology; D002470:Cell Survival / Q000276:immunology; D002478:Cells, Cultured; D006801:Humans; D007424:Intracellular Fluid / Q000276:immunology / Q000378:metabolism; D009000:Monocytes / Q000166:cytology / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology*
D000936:Antigen-Antibody Complex