Neutrophil migration towards C5a and CXCL8 is prevented by non-steroidal anti-inflammatory drugs via inhibition of different pathways
| Autor: | Bertolotto, Maria, Contini, Paola, Ottonello, Luciano, Pende, Aldo, Dallegri, Franco, Montecucco, Fabrizio |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
musculoskeletal diseases
ddc:616 Adult Phosphatidylinositol 3-Kinases/antagonists & inhibitors/metabolism Dose-Response Relationship Drug Neutrophils Anti-Inflammatory Agents Non-Steroidal Interleukin-8 Complement C5a/metabolism Complement C5a Anti-Inflammatory Agents Non-Steroidal/pharmacology Middle Aged Research Papers Healthy Volunteers Neutrophils/cytology/drug effects/metabolism Chemotaxis Leukocyte Phosphatidylinositol 3-Kinases Structure-Activity Relationship Young Adult Proto-Oncogene Proteins c-akt/antagonists & inhibitors/metabolism Interleukin-8/metabolism Humans Chemotaxis Leukocyte/drug effects Proto-Oncogene Proteins c-akt Phosphoinositide-3 Kinase Inhibitors |
| Zdroj: | British Journal of Pharmacology, Vol. 171, No 14 (2014) pp. 3376-3393 |
| ISSN: | 0007-1188 |
| Popis: | BACKGROUND AND PURPOSE:Non-steroidal anti-inflammatory drugs (NSAIDs) have been shown to induce PG-independent anti-inflammatory actions. Here, we investigated the role of three different NSAIDs (naproxen, ibuprofen and oxaprozin) on neutrophil responses to CXCL8 and C5a. EXPERIMENTAL APPROACH:Human neutrophils were isolated from healthy volunteers by dextran and Ficoll-Hypaque density gradients. Neutrophils were pre-incubated with different concentrations (1-100 µM) of NSAIDs or kinase inhibitors. Neutrophil degranulation into supernatants was tested by elisa and zymography. Neutrophil chemotaxis was determined using Boyden chambers. F-actin polymerization was determined by Alexa-Fluor 488-conjugated phalloidin fluorescent assay. Integrin expression was assessed by flow cytometry. The phosphorylation of intracellular kinases was studied by Western blot. KEY RESULTS:Pretreatment with NSAIDs did not affect neutrophil degranulation, but inhibited neutrophil migration and polymerization of F-actin, in response to CXCL8 and C5a. Pretreatment with different NSAIDs prevented C5a-induced integrin (CD11b) up-regulation, while only ibuprofen reduced CXCL8-induced CD11b up-regulation. Pre-incubation with naproxen or oxaprozin, but not ibuprofen, inhibited the PI3K/Akt-dependent chemotactic pathways. Both endogenous (released in cell supernatants) or exogenous (added to cell cultures) PGE2 did not affect C5a- or CXCL8-induced activities. Short-term incubation with NSAIDs did not affect neutrophil PGE2 release. CONCLUSION AND IMPLICATIONS:Treatment with NSAIDs reduced C5a- and CXCL8-induced neutrophil migration and F-actin polymerization via different mechanisms. Inhibition by ibuprofen was associated with integrin down-regulation, while naproxen and oxaprozin blocked the PI3K/Akt pathway. Both NSAID actions were independent of COX inhibition and PGE2 release. |
| Databáze: | OpenAIRE |
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