Delayed apoptosis of human monocytes exposed to immune complexes is reversed by oxaprozin: role of the Akt/IkappaB kinase/nuclear factor kappaB pathway.
OBJECTIVE
Monocytes-macrophages play a key role in the initiation and persistence of inflammatory reactions. Consequently, these cells represent an attractive therapeutic target for switching off overwhelming inflammatory responses. Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most common drugs for the symptomatic treatment of rheumatic diseases. Their effects have been explained on the basis of cyclooxygenase (COX) inhibition. However, some of the actions of these drugs are not related to inhibition of prostaglandin synthesis.


METHODS
We examined the effect of oxaprozin on apoptosis of immune complex-activated monocytes in comparison with drugs of the same class, and the signalling pathway that leads activated monocytes exposed to oxaprozin to apoptosis. In particular, we studied the activity of caspase-3, the involvement of IkappaB kinase (IKK)-nuclear factor kappaB (NF-kappaB) system and the activity of X-linked mammalian inhibitor of apoptosis protein (XIAP), Akt and mitogen-activated protein kinase (MAPK) in activated monocytes in the presence of oxaprozin.


RESULTS
Immune complexes caused the inhibition of monocyte apoptosis. Oxaprozin reversed in a dose-dependent manner immune complex-induced survival of monocytes, without affecting the apoptosis of resting cells. Other NSAIDs are ineffective. The activity of oxaprozin was related to inhibition of Akt activation that, in turn, prevented p38 MAPK, IKK and NF-kappaB activation. Consistently, the inhibition of NF-kappaB activation reduced the production of the anti-apoptotic molecule XIAP, leading to uncontrolled activity of caspase 3.


CONCLUSIONS
These results suggest that oxaprozin exerts its anti-inflammatory activity also through COX-independent pathways. It is likely that oxaprozin-mediated inhibition of the Akt/IKK/NF-kappaB pathway contributes to its anti-inflammatory properties.
Ottonello
Luciano
L
First Medical Clinic, Laboratory of Phagocyte Physiopathology and Inflammation, Department of Internal Medicine, University of Genoa, Genoa, Italy. otto@unige.it
Bertolotto
Maria
M
Montecucco
Fabrizio
F
Bianchi
Giordano
G
Dallegri
Franco
F