Oxaprozin-induced apoptosis on CD40 ligand-treated human primary monocytes is associated with the modulation of defined intracellular pathways.
The modulation of CD40L activity might represent a promising therapeutic target to reduce monocyte inflammatory functions in chronic diseases, such as rheumatoid arthritis. In the present study, we investigated the possible influence of nonsteroidal anti-inflammatory drugs (NSAIDs) on CD40L-induced monocyte survival. Monocytes were isolated from buffy coats by using Ficoll-Percoll gradients. Monocyte apoptosis was evaluated by fluorescence microscopy on cytopreps stained with acridine orange or using flow cytometry analysis of Annexin-V and Propidium Iodide staining. Akt and NF-kappaB activation was assessed using western blot. Caspase 3 activity was determined spectrophotometrically. Among different NSAIDs, only oxaprozin dose-dependently increased apoptosis of CD40L-treated monocytes. Oxaprozin pro-apoptotic activity was associated with the inhibition of CD40L-triggered Akt and NF-kappaB phosphorylation and the activation of caspase 3. In conclusion, our data suggest that oxaprozin-induced apoptosis in CD40L-treated human monocytes is associated with previously unknown cyclooxygenase (COX)-independent pathways. These intracellular proteins might be promising pharmacological targets to increase apoptosis in CD40L-treated monocytes.
Montecucco
Fabrizio
F
Division of Cardiology, Faculty of Medicine, Foundation for Medical Researches, University Hospital of Geneva, 1211 Geneva, Switzerland. fabrizio.montecucco@medecine.unige.ch
Bertolotto
Maria
M
Ottonello
Luciano
L
Quercioli
Alessandra
A
Mach
François
F
Dallegri
Franco
F
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D023201:CD40 Ligand / Q000097:blood / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D006801:Humans; D007249:Inflammation / Q000097:blood; D020928:Mitogen-Activated Protein Kinases / Q000097:blood; D009000:Monocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D052002:NF-kappa B p50 Subunit / Q000097:blood; D000077431:Oxaprozin; D019869:Phosphatidylinositol 3-Kinases / Q000097:blood; D010766:Phosphorylation; D011422:Propionates / Q000494:pharmacology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000097:blood; D051057:Proto-Oncogene Proteins c-akt / Q000097:blood; D015398:Signal Transduction
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D052002:NF-kappa B p50 Subunit; C489548:NFKB1 protein, human; D011422:Propionates; D023201:CD40 Ligand; D011451:Prostaglandin-Endoperoxide Synthases; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; D053148:Caspase 3; D000077431:Oxaprozin