Delayed apoptosis of human monocytes exposed to immune complexes is reversed by oxaprozin: role of the Akt/IκB kinase/nuclear factor κB pathway

Abstract

Background and purpose: 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. Experimental approach: 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 IkB kinase (IKK)-nuclear factor kB (NF-kB) 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. Key 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-kB activation. Consistently, the inhibition of NF-kB activation reduced the production of the anti-apoptotic molecule XIAP, leading to uncontrolled activity of caspase 3. Conclusions and implications:These results suggest that oxaprozin exerts its anti-inflammatory activity also through COXindependent pathways. It is likely that oxaprozin-mediated inhibition of the Akt/IKK/NF-kB pathway contributes to its anti-inflammatory properties. Pharmacology (2009) 157, 294-306; doi:10.1111/j.1476-5381.2009 published online 26 March 2009 Keywords: apoptosis; Akt; IKK; NF-kB; NSAIDs; oxaprozin; monocytes; immune complexes Abbreviations: COX, cyclooxygenase; ERK, extracellular signal-regulated kinase; FcR, fragment crystallizable receptor; IC, immune complex; IKK, IkB kinase; IL, interleukin; JNK, Jun N-terminal kinase; MAPK, mitogen-activated protein kinase; MCP-1, monocyte chemotactic protein 1; M-CSF, macrophage-colony stimulating factor; NF-kB, nuclear factor kB; NSAIDs, non-steroidal anti-inflammatory drugs; TNF-a, tumour necrosis factor-a; XIAP, X-linked mammalian inhibitor of apoptosis protein British Journal of IntroductionThe inflammation that characterizes rheumatic diseases is usually accompanied by swelling, stiffness and considerable pain which can limit the ability to perform daily activities, reduce overall joint functions and negatively interfere with health-related quality of life (Pollard et al., 2005;Scott et al., 2005). Understanding the molecular mechanisms that underpin the processes of inflammation and pain is the topic of considerable research, with t...

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