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Neutrophil migration towards C5a and CXCL8 is prevented by non-steroidal anti-inflammatory drugs via inhibition of different pathways

Bertolotto, Maria
Contini, Paola
Ottonello, Luciano
Pende, Aldo
Dallegri, Franco
Published in British Journal of Pharmacology. 2014, vol. 171, no. 14, p. 3376-3393
Abstract 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.
Keywords AdultAnti-Inflammatory Agents, Non-Steroidal/pharmacologyChemotaxis, Leukocyte/drug effectsComplement C5a/metabolismDose-Response Relationship, DrugHealthy VolunteersHumansInterleukin-8/metabolismMiddle AgedNeutrophils/cytology/drug effects/metabolismPhosphatidylinositol 3-Kinases/antagonists & inhibitors/metabolismProto-Oncogene Proteins c-akt/antagonists & inhibitors/metabolismStructure-Activity RelationshipYoung Adult
PMID: 24597536
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Research group L'athérosclérose et ses complications cliniques (591)
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BERTOLOTTO, Maria et al. Neutrophil migration towards C5a and CXCL8 is prevented by non-steroidal anti-inflammatory drugs via inhibition of different pathways. In: British Journal of Pharmacology, 2014, vol. 171, n° 14, p. 3376-3393. doi: 10.1111/bph.12670 https://archive-ouverte.unige.ch/unige:78056

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Deposited on : 2015-12-02

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